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imtoken钱包下载新版本|bone

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2024-03-07 17:28:55

BONE中文(简体)翻译：剑桥词典

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英语-中文（简体）

bone 在英语-中文（简体）词典中的翻译

bonenoun [ C or U ] uk

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/bəʊn/ us

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/boʊn/

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B1 any of the hard parts inside a human or animal that make up its frame

骨，骨头

The child was so thin that you could see her bones.

这孩子瘦得可怜，都能看见她的骨头。

human/animal bones

人／动物的骨头

B1 the bone in meat or fish

肉骨;鱼刺

There's still a lot of meat left on the bone - shall I slice some off for you?

骨头上还有许多肉——要我替你切一些下来吗？

I don't like fish because I hate the bones.

我不喜欢吃鱼，因为我讨厌鱼刺。

更多范例减少例句A fish bone got stuck in my throat.He's broken a bone in his wrist.Doctors have replaced the top of his hip bone with a metal sphere.The soldiers discovered a pile of human skulls and bones.Doctors inserted a metal pin in his leg to hold the bones together.

习语

bone dry

bone idle

a bone of contention

have a bone to pick with someone

make no bones about something

to the bone

boneverb uk

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/bəʊn/ us

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/boʊn/

bone verb

(SEX)

[ I or T ] offensive to have sex with someone

与…性交

bone verb

(FOOD)

[ T ] to take the bones out of something

剔去…的骨头

The chef bones the fish before grilling it.

厨师烤鱼前剔除了鱼骨。

短语动词

bone up

(bone在剑桥英语-中文（简体）词典的翻译 © Cambridge University Press)

B1,B1

bone的翻译

中文（繁体）

骨，骨頭, 肉骨, 魚骨…

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西班牙语

hueso, heso, espina…

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葡萄牙语

osso, espinha, osso [masculine]…

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मानव किंवा प्राण्याच्या आतील कोणताही कठीण भाग जो त्याची शरीर रचना बनवतो, मांस किंवा माशांमधील हाड…

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骨, 骨（ほね）…

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kemik, kılçıklarını ayıklamak, kemiklerini ayırmak…

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os [masculine], os, désosser…

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os…

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been, uitbenen, ontgraten…

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ஒரு மனிதன் அல்லது விலங்கின் உள்ளே உள்ள கடினமான பாகங்கள் அவற்றின் கட்டமைப்பை உருவாக்குகின்றன, இறைச்சி அல்லது மீனில் உள்ள எலும்பு…

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हड्डी, (माँस या मछली में) हड्डी…

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હાડકાં, માંસ અથવા માછલીમાં રહેલું હાડકું…

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knogle, ben…

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ben, bena [ur]…

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tulang, mengeluarkan tulang…

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der Knochen, die Knochen/Gräten herausnehmen…

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ben [neuter], bein, ta bein ut av…

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ہڈی, گوشت میں ہڈی یامچھلی میں کانٹا…

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кістка, виймати кістки…

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кость, вынимать кости…

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బొక్క, యముక…

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عَظْم…

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হাড়, মাংসের হাড় বা মাছের কাঁটা…

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kost, vykostit…

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tulang, membuang tulang…

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กระดูก, ถอดกระดูก…

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bộ xương, xương, gỡ xương…

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kość, ość, filetować…

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뼈…

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osso, spina, lisca…

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bonded

bondholder

bonding

bonds phrase

bone

bone china

bone dry idiom

bone idle idiom

bone marrow

bone更多的中文(简体)翻译

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T-bone

bone-dry

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bone marrow

funny bone

bone-chilling

T-bone steak

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词组动词

bone up

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惯用语

bone dry idiom

bone dry, at as dry as a bone idiom

bone idle idiom

to the bone idiom

be skin and bone(s) idiom

as dry as a bone idiom

a bone of contention idiom

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“每日一词”

veggie burger

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/ˈvedʒ.i ˌbɜː.ɡər/

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/ˈvedʒ.i ˌbɝː.ɡɚ/

a type of food similar to a hamburger but made without meat, by pressing together small pieces of vegetables, seeds, etc. into a flat, round shape

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Mechanisms of bone development and repair | Nature Reviews Molecular Cell Biology

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Mechanisms of bone development and repair

Ankit Salhotra

ORCID: orcid.org/0000-0001-6107-66561,2 na1, Harsh N. Shah

ORCID: orcid.org/0000-0002-4371-92051,2 na1, Benjamin Levi3 & …Michael T. Longaker

ORCID: orcid.org/0000-0003-1430-89141,2 Show authors

Nature Reviews Molecular Cell Biology

volume 21, pages 696–711 (2020)Cite this article

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Adult stem cellsCell biologyMolecular biologyOrganogenesisRegeneration

AbstractBone development occurs through a series of synchronous events that result in the formation of the body scaffold. The repair potential of bone and its surrounding microenvironment — including inflammatory, endothelial and Schwann cells — persists throughout adulthood, enabling restoration of tissue to its homeostatic functional state. The isolation of a single skeletal stem cell population through cell surface markers and the development of single-cell technologies are enabling precise elucidation of cellular activity and fate during bone repair by providing key insights into the mechanisms that maintain and regenerate bone during homeostasis and repair. Increased understanding of bone development, as well as normal and aberrant bone repair, has important therapeutic implications for the treatment of bone disease and ageing-related degeneration.

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Fig. 1: Bone homeostasis.Fig. 2: Skeletal stem cell hierarchy.Fig. 3: Long bone anatomy.Fig. 4: Developmental signalling pathways regulating osteoblast differentiation.Fig. 5: Continuum of bone disorders.

ReferencesAmbrosi, T. H., Longaker, M. T. & Chan, C. K. F. A revised perspective of skeletal stem cell biology. Front. Cell Dev. Biol. 7, 189 (2019).PubMed

PubMed Central

Google Scholar

Murphy, M. P. et al. The role of skeletal stem cells in the reconstruction of bone defects. J. Craniofac. Surg. 28, 1136–1141 (2017).PubMed

PubMed Central

Google Scholar

Long, F. Building strong bones: molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol. 13, 27–38 (2012).CAS

Google Scholar

Bianco, P. & Robey, P. G. Skeletal stem cells. Development 142, 1023–1027 (2015).CAS

PubMed

PubMed Central

Google Scholar

Garnero, P., Sornay-Rendu, E., Chapuy, M. C. & Delmas, P. D. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J. Bone Miner. Res. 11, 337–349 (2009).

Google Scholar

Soltanoff, C. S., Yang, S., Chen, W. & Li, Y. P. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit. Rev. Eukaryot. Gene Expr. 19, 1–46 (2009).CAS

PubMed

PubMed Central

Google Scholar

Compton, J. T. & Lee, F. Y. Current concepts review: a review of osteocyte function and the emerging importance of sclerostin. J. Bone Joint Surg. Am. 96, 1659–1668 (2014).PubMed

PubMed Central

Google Scholar

Van Bezooijen, R. L. et al. Sclerostin Is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J. Exp. Med. 199, 805–814 (2004).PubMed

PubMed Central

Google Scholar

Robling, A. G. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283, 5866–5875 (2008).CAS

PubMed

Google Scholar

Tatsumi, S. et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 5, 464–475 (2007).CAS

PubMed

Google Scholar

Jacome-Galarza, C. E., Lee, S. K., Lorenzo, J. A. & Aguila, H. L. Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J. Bone Miner. Res. 28, 1203–1213 (2013).CAS

PubMed

PubMed Central

Google Scholar

Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).CAS

PubMed

Google Scholar

Dougall, W. C. et al. RANK is essential for osteoclast and lymph node development. Genes. Dev. 13, 2412–2424 (1999).CAS

PubMed

PubMed Central

Google Scholar

Xu, F. & Teitelbaum, S. L. Osteoclasts: new insights. Bone Res. 1, 11–26 (2013).CAS

PubMed Central

Google Scholar

Meyers, C. et al. Heterotopic ossification: a comprehensive review. JBMR Plus 3, e10172 (2019).PubMed

PubMed Central

Google Scholar

Dallas, S. L., Xie, Y., Shiflett, L. A. & Ueki, Y. Mouse Cre models for the study of bone diseases. Curr. Osteoporos. Rep. 16, 466–477 (2018).PubMed

PubMed Central

Google Scholar

Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999). This work establishes the potential for MSCs to differentiate into bone, cartilage and fat.CAS

PubMed

Google Scholar

Chen, Q. et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ. 23, 1128–1139 (2016).CAS

PubMed

PubMed Central

Google Scholar

Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Prolif. 3, 393–403 (1970).CAS

Google Scholar

Friedenstein, A. J., Chailakhyan, R. K. & Gerasimov, U. V. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Prolif. 20, 263–272 (1987).CAS

Google Scholar

Friedenstein, A. J. Osteogenic stem cells in the bone marrow. Bone Miner. Res. https://doi.org/10.1016/b978-0-444-81371-8.50012-1 (1990).Article

Google Scholar

Wei, J. et al. Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell 161, 1576–1591 (2015).CAS

PubMed

PubMed Central

Google Scholar

Wang, T., Zhang, X. & Bikle, D. D. Osteogenic differentiation of periosteal cells during fracture healing. J. Cell Physiol. 232, 913–921 (2017).CAS

PubMed

Google Scholar

Ackema, K. B. & Charité, J. Mesenchymal stem cells from different organs are characterized by distinct topographic Hox codes. Stem Cell Dev. 17, 979–991 (2008).CAS

Google Scholar

Rux, D. R. et al. Regionally restricted Hox function in adult bone marrow multipotent mesenchymal stem/stromal cells. Dev. Cell 39, 653–666 (2016).CAS

PubMed

PubMed Central

Google Scholar

Nelson, L. T., Rakshit, S., Sun, H. & Wellik, D. M. Generation and expression of a Hoxa11eGFP targeted allele in mice. Dev. Dyn. 237, 3410–3416 (2008).CAS

PubMed

PubMed Central

Google Scholar

Swinehart, I. T., Schlientz, A. J., Quintanilla, C. A., Mortlock, D. P. & Wellik, D. M. Hox11 genes are required for regional patterning and integration of muscle, tendon and bone. Development 140, 4574–4582 (2013).CAS

PubMed

PubMed Central

Google Scholar

Pineault, K. M., Song, J. Y., Kozloff, K. M., Lucas, D. & Wellik, D. M. Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life. Nat. Commun. 10, 3168 (2019).PubMed

PubMed Central

Google Scholar

Rux, D. R. & Wellik, D. M. Hox genes in the adult skeleton: novel functions beyond embryonic development. Dev. Dyn. 246, 310–317 (2017).CAS

PubMed

PubMed Central

Google Scholar

Chan, C. K. F. et al. Identification and specification of the mouse skeletal stem cell. Cell 160, 285–298 (2015). The work is the first to isolate the SSC in mice, which has the differentiation capacity to be restricted to bone, cartilage,and bone stroma.CAS

PubMed

PubMed Central

Google Scholar

Chan, C. K. F. et al. Identification of the human skeletal stem cell. Cell 175, 43–56 (2018).CAS

PubMed

PubMed Central

Google Scholar

Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).CAS

PubMed

Google Scholar

Kassem, M. & Bianco, P. Skeletal stem cells in space and time. Cell 160, 17–19 (2015).CAS

PubMed

Google Scholar

Bianco, P. Stem cells and bone: a historical perspective. Bone 70, 2–9 (2015).PubMed

Google Scholar

Ueno, H. & Weissman, I. L. Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev. Cell 11, 519–533 (2006).CAS

PubMed

Google Scholar

Worthley, D. L. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160, 269–284 (2015).CAS

PubMed

PubMed Central

Google Scholar

Chan, C. K. F. et al. Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells. Proc. Natl Acad. Sci. USA 110, 12643–12648 (2013).CAS

PubMed

Google Scholar

Berendsen, A. D. & Olsen, B. R. Bone development. Bone 80, 14–18 (2015).CAS

PubMed

PubMed Central

Google Scholar

Marecic, O. et al. Identification and characterization of an injury-induced skeletal progenitor. Proc. Natl Acad. Sci. USA 112, 9920–9925 (2015).CAS

PubMed

Google Scholar

Tevlin, R. et al. Pharmacological rescue of diabetic skeletal stem cell niches. Sci. Transl Med. 9, eaag2809 (2017).PubMed

PubMed Central

Google Scholar

Ransom, R. C. et al. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature 563, 514–521 (2018).CAS

PubMed

PubMed Central

Google Scholar

Mizuhashi, K. et al. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 563, 254–258 (2018).CAS

PubMed

PubMed Central

Google Scholar

Debnath, S. et al. Discovery of a periosteal stem cell mediating intramembranous bone formation. Nature 562, 133–139 (2018).CAS

PubMed

PubMed Central

Google Scholar

Jia, G. et al. Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement. Nat. Commun. 9, 4877 (2018).PubMed

PubMed Central

Google Scholar

Baker, S., Rogerson, C., Hayes, A., Sharrocks, A. & Rattray, M. Classifying cells with Scasat, a single-cell ATAC-seq analysis tool. Nucleic Acids Res. 47, e10 (2019).PubMed

Google Scholar

Le Douarin, N. M. & Smith, J. Development of the peripheral nervous system from the neural crest. Annu. Rev. Cell Biol. 4, 375–404 (1988).PubMed

Google Scholar

Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb Perspect. Biol. 5, a008334 (2013).PubMed

PubMed Central

Google Scholar

Kronenberg, H. M. Developmental regulation of the growth plate. Nature. 423, 332–336 (2003).CAS

PubMed

Google Scholar

Maes, C. & Kronenberg, H. M. Postnatal bone growth: growth plate biology, bone formation, and remodeling. pediatric. Bone https://doi.org/10.1016/B978-0-12-382040-2.10004-8 (2012).Article

Google Scholar

Lefebvr, E. V. & Dvir-Ginzberg, M. SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect. Tissue Res. 58, 2–14 (2017).

Google Scholar

Lovell-Badge, R. The early history of the Sox genes. Int. J. Biochem. Cell Biol. 42, 378–380 (2010).CAS

PubMed

Google Scholar

Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. & De Crombrugghe, B. Sox9 is required for cartilage formation. Nat. Genet. 22, 85–89 (1999).CAS

PubMed

Google Scholar

Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. & De Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813–2828 (2002).CAS

PubMed

PubMed Central

Google Scholar

Henry, S. P., Liang, S., Akdemir, K. C. & De Crombrugghe, B. The postnatal role of Sox9 in cartilage. J. Bone Miner. Res. 27, 2511–2525 (2012).CAS

PubMed

PubMed Central

Google Scholar

Schafer, A. J. et al. Campomelic dysplasia with XY sex reversal: diverse phenotypes resulting from mutations in a single gene. Ann. N. Y. Acad. Sci. 785, 137–149 (1996).CAS

PubMed

Google Scholar

Gentilin, B. et al. Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene. Ultrasound Obstet. Gynecol. 36, 315–323 (2010).CAS

PubMed

Google Scholar

Komori, T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 339, 189–195 (2010).CAS

PubMed

Google Scholar

Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997).CAS

PubMed

Google Scholar

Harada, H. et al. Cbfa1 isoforms exert functional differences in osteoblast differentiation. J. Biol. Chem. 274, 6972–6978 (1999).CAS

PubMed

Google Scholar

Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997). This work establishes RUNX2 as an essential transcription factor for osteoblast differentiation.CAS

PubMed

Google Scholar

Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997).CAS

PubMed

Google Scholar

Inada, M. et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev. Dyn. 214, 279–290 (1999).CAS

PubMed

Google Scholar

Takarada, T. et al. An analysis of skeletal development in osteoblast-specific and chondrocyte-specific runt-related transcription factor-2 (Runx2) knockout mice. J. Bone Miner. Res. 28, 2064–2069 (2013).CAS

PubMed

Google Scholar

Maruyama, Z. et al. Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev. Dyn. 236, 1876–1890 (2007).CAS

PubMed

Google Scholar

Sinha, K. M. & Zhou, X. Genetic and molecular control of osterix in skeletal formation. J. Cell Biochem. 114, 975–984 (2013).CAS

PubMed

PubMed Central

Google Scholar

Karsenty, G. Minireview: tranzscriptional control of osteoblast differentiation. Endocrinology 142, 2731–2733 (2001).CAS

PubMed

Google Scholar

Nakashima, K. & De Crombrugghe, B. Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet. 19, 458–466 (2003).CAS

PubMed

Google Scholar

Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002). This work establishes the temporal coordination between OSX and RUNX2 activation for osteoblast differentiation.CAS

PubMed

Google Scholar

Yang, X. & Karsenty, G. Transcription factors in bone: developmental and pathological aspects. Trends Mol. Med. 8, 340–345 (2002).CAS

PubMed

Google Scholar

Zhou, X. et al. Multiple functions of osterix are required for bone growth and homeostasis in postnatal mice. Proc. Natl Acad. Sci. USA 107, 12919–12924 (2010).CAS

PubMed

Google Scholar

Liu, T. M. & Lee, E. H. Transcriptional regulatory cascades in Runx2-dependent bone development. Tissue Eng. Part B Rev. 19, 254–263 (2013).PubMed

Google Scholar

St-Arnaud, R. & Hekmatnejad, B. Combinatorial control of ATF4-dependent gene transcription in osteoblasts. Ann. N. Y. Acad. Sci. 1237, 11–18 (2011).CAS

PubMed

Google Scholar

Yang, X. et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry syndrome. Cell 117, 387–398 (2004).CAS

PubMed

Google Scholar

Jing, D. et al. The role of microRNAs in bone remodeling. Int. J. Oral. Sci. 7, 131–143 (2015).CAS

PubMed

PubMed Central

Google Scholar

Xiao, G. et al. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J. Biol. Chem. 280, 30689–30696 (2005).CAS

PubMed

Google Scholar

Wagner, E. F. Functions of AP1 (Fos/Jun) in bone development. Ann. Rheum. Dis. 61, ii40–ii42 (2002).CAS

PubMed

PubMed Central

Google Scholar

Kenner, L. et al. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J. Cell Biol. 164, 613–623 (2004).CAS

PubMed

PubMed Central

Google Scholar

Zambotti, A., Makhluf, H., Shen, J. & Ducy, P. Characterization of an osteoblast-specific enhancer element in the CBFA1. Gene 277, 41497–41506 (2002).CAS

Google Scholar

Jochum, W. et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat. Med. 6, 980–984 (2000).CAS

PubMed

Google Scholar

Bozec, A. et al. Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. J. Cell Biol. 190, 1093–1106 (2010).CAS

PubMed

PubMed Central

Google Scholar

Nüsslein-volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in drosophila. Nature. 287, 795–801 (1980).PubMed

Google Scholar

McMahon, A. P., Ingham, P. W. & Tabin, C. J. 1 Developmental roles and clinical significance of Hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114 (2003).CAS

PubMed

Google Scholar

Ocbina, P. J. R. & Anderson, K. V. Intraflagellar transport, Cilia, and mammalian hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev. Dyn. 237, 2030–2038 (2008).PubMed

PubMed Central

Google Scholar

Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).CAS

PubMed

Google Scholar

Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science. 317, 372–376 (2007).CAS

PubMed

Google Scholar

Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature. 437, 1018–1021 (2005).CAS

PubMed

Google Scholar

Towers, M., Mahood, R., Yin, Y. & Tickle, C. Integration of growth and specification in chick wing digit-patterning. Nature 452, 882–886 (2008).CAS

PubMed

Google Scholar

Chinnaiya, K., Tickle, C. & Towers, M. Sonic hedgehog-expressing cells in the developing limb measure time by an intrinsic cell cycle clock. Nat. Commun. 5, 4230 (2014).CAS

PubMed

PubMed Central

Google Scholar

Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000).CAS

PubMed

Google Scholar

Mo, R. et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124, 113–123 (1997).CAS

PubMed

Google Scholar

Park, H. et al. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127, 1593–1605 (2000).CAS

PubMed

Google Scholar

Hojo, H. et al. Gli1 protein participates in hedgehog-mediated specification of osteoblast lineage during endochondral ossification. J. Biol. Chem. 287, 17860–17869 (2012).CAS

PubMed

PubMed Central

Google Scholar

Amano, K., Densmore, M., Nishimura, R. & Lanske, B. Indian hedgehog signaling regulates transcription and expression of collagen type X via Runx2/Smads interactions. J. Biol. Chem. 289, 24898–24910 (2014).CAS

PubMed

PubMed Central

Google Scholar

Jemtland, R., Divieti, P., Lee, K. & Segre, G. V. Hedgehog promotes primary osteoblast differentiation and increases PTHrP mRNA expression and iPTHrP secretion. Bone 32, 611–620 (2003).CAS

PubMed

Google Scholar

Long, F. & Linsenmayer, T. F. Regulation of growth region cartilage proliferation and differentiation by perichondrium. Development 125, 1067–1073 (1998).CAS

PubMed

Google Scholar

Mak, K. K., Chen, M. H., Day, T. F., Chuang, P. T. & Yang, Y. Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 133, 3695–3707 (2006).CAS

PubMed

Google Scholar

Day, T. F. & Yang, Y. Wnt and hedgehog signaling pathways in bone development. J. Bone Joint Surg. Ser. Am. 90, 19–24 (2008).

Google Scholar

Hojo, H. et al. Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium. J. Biol. Chem. 288, 9924–9932 (2013).CAS

PubMed

PubMed Central

Google Scholar

Schroeter, E. H., Kisslinger, J. A. & Kopan, R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998).CAS

PubMed

Google Scholar

Zanotti, S. & Canalis, E. Notch signaling and the skeleton. Endocr. Rev. 37, 223–253 (2016).CAS

PubMed

PubMed Central

Google Scholar

Tu, X. et al. Physiological Notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet. 8, e1002577 (2012).CAS

PubMed

PubMed Central

Google Scholar

Hilton, M. J. et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat. Med. 14, 306–314 (2008).CAS

PubMed

PubMed Central

Google Scholar

Engin, F. et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat. Med. 14, 299–305 (2008).CAS

PubMed

PubMed Central

Google Scholar

Canalis, E., Parker, K., Feng, J. Q. & Zanotti, S. Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154, 623–634 (2013).CAS

PubMed

Google Scholar

Zanotti, S. & Canalis, E. Notch1 and Notch2 expression in osteoblast precursors regulates femoral microarchitecture. Bone 62, 22–28 (2014).CAS

PubMed

PubMed Central

Google Scholar

Kim, J. B. et al. Bone regeneration is regulated by Wnt signaling. J. Bone Miner. Res. 22, 1913–1923 (2007).CAS

PubMed

Google Scholar

Huelsken, J. & Birchmeier, W. New aspects of Wnt signaling pathways in higher vertebrates. Curr. Opin. Genet. Dev. 11, 547–553 (2001).CAS

PubMed

Google Scholar

Williams, B. O. & Insogna, K. L. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J. Bone Miner. Res. 24, 171–178 (2009).CAS

PubMed

Google Scholar

Joiner, D. M., Ke, J., Zhong, Z., Xu, H. E. & Williams, B. O. LRP5 and LRP6 in development and disease. Trends Endocrinol. Metab. 24, 31–39 (2013).CAS

PubMed

PubMed Central

Google Scholar

Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).CAS

PubMed

Google Scholar

Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).CAS

PubMed

Google Scholar

Little, R. D. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70, 11–19 (2002).CAS

PubMed

Google Scholar

Houschyar, K. S. et al. Wnt pathway in bone repair and regeneration – what do we know so far. Front. Cell Dev. Biol. 6, 170 (2019).PubMed

PubMed Central

Google Scholar

Minear, S. et al. Wnt proteins promote bone regeneration. Sci. Transl Med. 2, 29ra30 (2010).PubMed

Google Scholar

Poole, K. E. S. et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 19, 1842–1844 (2005).CAS

PubMed

Google Scholar

Ai, M., Holmen, S. L., Van Hul, W., Williams, B. O. & Warman, M. L. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol. Cell Biol. 25, 4946–4955 (2005).CAS

PubMed

PubMed Central

Google Scholar

Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68, 577–589 (2001).CAS

PubMed

PubMed Central

Google Scholar

Holmen, S. L. et al. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J. Bone Miner. Res. 19, 2033–2040 (2004).CAS

PubMed

Google Scholar

Kubota, T. et al. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J. Bone Miner. Res. 23, 1661–1671 (2008).CAS

PubMed

Google Scholar

Lin, G. L. & Hankenson, K. D. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J. Cell Biochem. 112, 3491–3501 (2011).CAS

PubMed

PubMed Central

Google Scholar

Wu, M., Chen, G. & Li, Y. P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4, 16009 (2016).PubMed

PubMed Central

Google Scholar

Itasaki, N. & Hoppler, S. Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev. Dyn. 239, 16–33 (2010).CAS

PubMed

Google Scholar

Luo, Q. et al. Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells. J. Biol. Chem. 279, 55958–55968 (2004).CAS

PubMed

Google Scholar

Si, W. et al. CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol. Cell Biol. 26, 2955–2964 (2006).CAS

PubMed

PubMed Central

Google Scholar

Boland, G. M., Perkins, G., Hall, D. J. & Tuan, R. S. Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J. Cell Biochem. 93, 1210–1230 (2004).CAS

PubMed

Google Scholar

Chen, Y. et al. β-Catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation. J. Biol. Chem. 282, 526–533 (2007).CAS

PubMed

Google Scholar

Zhang, M. et al. BMP-2 modulates β-catenin signaling through stimulation of Lrp5 expression and inhibition of β-TrCP expression in osteoblasts. J. Cell Biochem. 108, 896–905 (2009).CAS

PubMed

PubMed Central

Google Scholar

Wrana, J. L. et al. TGFβ signals through a heteromeric protein kinase receptor complex. Cell 71, 1003–1014 (1992).CAS

PubMed

Google Scholar

Schmierer, B. & Hill, C. S. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell Biol. 8, 970–982 (2007).CAS

PubMed

Google Scholar

Salazar, V. S., Gamer, L. W. & Rosen, V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12, 203–221 (2016).CAS

PubMed

Google Scholar

Katagiri, T. & Watabe, T. Bone morphogenetic proteins. Cold Spring Harb Perspect. Biol. https://doi.org/10.1101/cshperspect.a021899 (2016).Article

PubMed

PubMed Central

Google Scholar

Salazar, V. S. et al. Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche. eLife https://doi.org/10.7554/eLife.42386 (2019).Article

PubMed

PubMed Central

Google Scholar

Bandyopadhyay, A. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2, 2116–2130 (2006).CAS

Google Scholar

Tsuji, K. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 38, 1424–1429 (2006). This work demonstrates the role of reoccurring BMP signalling for limb development and fracture healing of the limb.CAS

PubMed

Google Scholar

Lim, J. et al. Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in mouse. Development 143, 339–347 (2016).CAS

PubMed

PubMed Central

Google Scholar

Fujii, M. et al. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol. Biol. Cell 10, 3801–3813 (1999).CAS

PubMed

PubMed Central

Google Scholar

Singhatanadgit, W. & Olsen, I. Endogenous BMPR-IB signaling is required for early osteoblast differentiation of human bone cells. Vitr. Cell Dev. Biol. Anim. 47, 251–259 (2011).CAS

Google Scholar

Yoshida, Y. et al. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103, 1085–1097 (2000).CAS

PubMed

Google Scholar

Zhang, Y. et al. Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments. Bone 88, 74–84 (2016).CAS

PubMed

PubMed Central

Google Scholar

Johnson, D. E. & Williams, L. T. Structural and functional diversity in the FGF receptor multigene family. Adv. Cancer Res. 60, 1–41 (1992).

Google Scholar

Ornitz, D. M. et al. Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271, 15292–15297 (1996).CAS

PubMed

Google Scholar

Ornitz, D. M. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor. Rev. 16, 205–213 (2005).CAS

PubMed

PubMed Central

Google Scholar

Montero, A. et al. Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J. Clin. Invest. 105, 1085–1093 (2000).CAS

PubMed

PubMed Central

Google Scholar

Zhou, M. et al. Fibroblast growth factor 2 control of vascular tone. Nat. Med. 4, 201–207 (1998).CAS

PubMed

PubMed Central

Google Scholar

Crossley, P. H., Minowada, G., MacArthur, C. A. & Martin, G. R. Roles for FGF8 in the induction, initiation, and maintenance of chick limb development. Cell 84, 127–136 (1996).CAS

PubMed

Google Scholar

Lewandoski, M., Sun, X. & Martin, G. R. Fgf8 signalling from the AER is essential for normal limb development. Nat. Genet. 26, 460–463 (2000).CAS

PubMed

Google Scholar

Martin, G. R. The roles of FGFs in the early development of vertebrate limbs. Genes Dev. 12, 1571–1586 (1998).CAS

PubMed

Google Scholar

Min, H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev. 12, 3156–3161 (1998).CAS

PubMed

PubMed Central

Google Scholar

Ohuchi, H. et al. The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. Development 124, 2235–2244 (1997).CAS

PubMed

Google Scholar

Mahmood, R. et al. A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth. Curr. Biol. 5, 797–806 (1995).CAS

PubMed

Google Scholar

Heikinheimo, M., Lawshé, A., Shackleford, G. M., Wilson, D. B. & MacArthur, C. A. Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system. Mech. Dev. 48, 129–138 (1994).CAS

PubMed

Google Scholar

Lin, J. M. et al. Actions of fibroblast growth factor-8 in bone cells in vitro. Am. J. Physiol. Endocrinol. Metab. 297, E142–E150 (2009).CAS

PubMed

Google Scholar

Yamaguchi, T. P., Conlon, R. A. & Rossant, J. Expression of the fibroblast growth factor receptor FGFR-1/flg during gastrulation and segmentation in the mouse embryo. Dev. Biol. 152, 75–88 (1992).CAS

PubMed

Google Scholar

Deng, C. et al. Fibroblast growth factor receptor-1 (FGFR-1) is essential for normal neural tube and limb development. Dev. Biol. 185, 42–54 (1997).CAS

PubMed

Google Scholar

Jacob, A. L., Smith, C., Partanen, J. & Ornitz, D. M. Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev. Biol. 296, 315–328 (2006).CAS

PubMed

PubMed Central

Google Scholar

Verheyden, J. M., Lewandoski, M., Deng, C., Harfe, B. D. & Sun, X. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development 132, 4235–4245 (2005).CAS

PubMed

PubMed Central

Google Scholar

Orr-Urtreger, A. et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev. Biol. 158, 475–486 (1993).CAS

PubMed

Google Scholar

Li, X. et al. Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body. J. Cell Biol. 153, 811–822 (2001).CAS

PubMed

PubMed Central

Google Scholar

Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K. & Lonai, P. Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc. Natl Acad. Sci. USA 95, 5082–5087 (1998).CAS

PubMed

Google Scholar

Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753–765 (1998).CAS

PubMed

Google Scholar

Wang, Y. et al. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development 132, 3537–3548 (2005).CAS

PubMed

Google Scholar

Claes, L., Recknagel, S. & Ignatius, A. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol. 8, 133–143 (2012).CAS

PubMed

Google Scholar

Glynne, A. J., Andrew, S. M., Freemont, A. J. & Marsh, D. R. Inflammatory cells in normal human fracture healing. Acta Orthop. 65, 462–466 (1994).

Google Scholar

Bolander, M. E. Regulation of fracture repair by growth factors. Exp. Biol. Med. 200, 165–170 (1992).CAS

Google Scholar

Croes, M. et al. Proinflammatory mediators enhance the osteogenesis of human mesenchymal stem cells after lineage commitment. PLoS ONE 10, e0132781 (2015).PubMed

PubMed Central

Google Scholar

Lu, L. Y. et al. Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway. J. Orthop. Res. 35, 2378–2385 (2017).CAS

PubMed

PubMed Central

Google Scholar

Bernhardsson, M. & Aspenberg, P. Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury. Acta Orthop. 89, 457–461 (2018).PubMed

PubMed Central

Google Scholar

Ono, T. et al. IL-17-producing γδT cells enhance bone regeneration. Nat. Commun. 7, 10928 (2016). This work shows that the presence of the proinflammatory cytokine IL-17, from the niche, aided in bone regrowth after injury.CAS

PubMed

PubMed Central

Google Scholar

Goerke, S. M., Obermeyer, J., Plaha, J., Stark, G. B. & Finkenzeller, G. Endothelial progenitor cells from peripheral blood support bone regeneration by provoking an angiogenic response. Microvasc. Res. 98, 40–47 (2015).CAS

PubMed

Google Scholar

Langen, U. H. et al. Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat. Cell Biol. 19, 189–201 (2017).CAS

PubMed

PubMed Central

Google Scholar

Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 507, 323–328 (2014).CAS

PubMed

PubMed Central

Google Scholar

Ramasamy, S. K., Kusumbe, A. P., Wang, L. & Adams, R. H. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. 507, 376–380 (2014).CAS

PubMed

PubMed Central

Google Scholar

Cao, J. et al. Sensory nerves affect bone regeneration in rabbit mandibular distraction osteogenesis. Int. J. Med. Sci. 16, 831–837 (2019).CAS

PubMed

PubMed Central

Google Scholar

Jones, R. E. et al. Skeletal stem cell-Schwann cell circuitry in Mandibular repair. Cell Rep. 28, 2757–2766.e5 (2019).CAS

PubMed

PubMed Central

Google Scholar

Park, B. W., Kim, J. R., Lee, J. H. & Byun, J. H. Expression of nerve growth factor and vascular endothelial growth factor in the inferior alveolar nerve after distraction osteogenesis. Int. J. Oral Maxillofac. Surg. 35, 624–630 (2006).PubMed

Google Scholar

Wang, L. et al. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J. Orthop. Res. 24, 2238–2245 (2006).CAS

PubMed

Google Scholar

Emara, K. M., Diab, R. A. & Emara, A. K. Recent biological trends in management of fracture non-union. World J. Orthop. 6, 623–628 (2015).PubMed

PubMed Central

Google Scholar

Panteli, M., Pountos, I., Jones, E. & Giannoudis, P. V. Biological and molecular profile of fracture non-union tissue: current insights. J. Cell Mol. Med. 19, 685–713 (2015).PubMed

PubMed Central

Google Scholar

Jones, A. L. et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects: a randomized, controlled trial. J. Bone Joint Surg. Ser. Am. 88, 1431–1441 (2006).

Google Scholar

Kawaguchi, H. et al. Local application of recombinant human fibroblast growth factor-2 on bone repair: a dose-escalation prospective trial on patients with osteotomy. J. Orthop. Res. 25, 480–487 (2007).CAS

PubMed

Google Scholar

Babcock, S. & Kellam, J. F. Hip fracture nonunions: diagnosis, treatment, and special considerations in elderly patients. Adv. Orthop. https://doi.org/10.1155/2018/1912762 (2018).Article

PubMed

PubMed Central

Google Scholar

Atanelov, Z. & Bentley, T. P. Greenstick fracture. StatPearls (2018).Kraft, C. T. et al. Trauma-induced heterotopic bone formation and the role of the immune system: a review. J. Trauma. Acute Care Surg. 80, 156–165 (2016).CAS

PubMed

PubMed Central

Google Scholar

Huang, H. et al. Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification. J. Orthop. Transl 12, 16–25 (2018).

Google Scholar

Sorkin, M. et al. Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing. Nat Commun. https://doi.org/10.1038/s41467-019-14172-4 (2020).This work determines CD47 activation as a therapeutic approach for heterotopic ossification formation during wound healing.Agarwal, S. et al. Disruption of neutrophil extracellular traps (NETs) links mechanical strain to post-traumatic inflammation. Front. Immunol. 10, 2148 (2019).CAS

PubMed

PubMed Central

Google Scholar

Torossian, F. et al. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. JCI Insight 2, e96034 (2017).PubMed Central

Google Scholar

Hwang, C. et al. Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification. Bone Res. 7, 36 (2019).CAS

PubMed

PubMed Central

Google Scholar

Hsieh, H. H. S. et al. Coordinating tissue regeneration through transforming growth factor-β activated kinase 1 inactivation and reactivation. Stem Cells 37, 766–778 (2019).CAS

PubMed

PubMed Central

Google Scholar

Raggatt, L. J. et al. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am. J. Pathol. 184, 3192–3204 (2014).CAS

PubMed

Google Scholar

Agarwal, S. et al. Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proc. Natl Acad. Sci. USA 113, E338–E347 (2016).CAS

PubMed

Google Scholar

Agarwal, S. et al. Scleraxis-lineage cells contribute to ectopic bone formation in muscle and tendon. Stem Cells 35, 705–710 (2017).CAS

PubMed

Google Scholar

Loder, S. J. et al. Characterizing the circulating cell populations in traumatic heterotopic ossification. Am. J. Pathol. 188, 2464–2473 (2018).CAS

PubMed

PubMed Central

Google Scholar

Dey, D. et al. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aaf1090 (2016).Article

PubMed

PubMed Central

Google Scholar

Kan, C. et al. Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone 109, 71–79 (2018).CAS

PubMed

Google Scholar

Eisner, C. et al. Murine tissue-resident PDGFRα+ fibro-adipogenic progenitors spontaneously acquire osteogenic phenotype in an altered inflammatory environment. J. Bone Miner. Res. (2020).Agarwal, S. et al. Analysis of bone-cartilage-stromal progenitor populations in trauma induced and genetic models of heterotopic ossification. Stem Cells 34, 1692–1701 (2016).CAS

PubMed

PubMed Central

Google Scholar

Agarwal, S. et al. Strategic targeting of multiple BMP receptors prevents trauma-induced heterotopic ossification. Mol. Ther. 25, 1974–1987 (2017).CAS

PubMed

PubMed Central

Google Scholar

Huber, A. K. et al. Immobilization after injury alters extracellular matrix and stem cell fate. J. Clin. Invest. https://doi.org/10.1172/JCI136142 (2020).Article

PubMed

PubMed Central

Google Scholar

Stepien, D. M. et al. Tuning macrophage phenotype to mitigate skeletal muscle fibrosis. J. Immunol. 204, 2203–2215 (2020).CAS

PubMed

Google Scholar

Peterson, J. R. et al. Effects of aging on osteogenic response and heterotopic ossification following burn injury in mice. Stem Cell Dev. 24, 205–213 (2015).CAS

Google Scholar

Ranganathan, K. et al. Role of gender in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation. Plast. Reconstr. Surg. 135, 1631–1641 (2015).CAS

PubMed

PubMed Central

Google Scholar

Akiyama, H. et al. Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. Proc. Natl Acad. Sci. USA 102, 14665–14670 (2005).CAS

PubMed

Google Scholar

Maes, C. et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell 19, 329–344 (2010).CAS

PubMed

PubMed Central

Google Scholar

Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 495, 227–230 (2013).CAS

PubMed

PubMed Central

Google Scholar

Xiong, J. et al. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS ONE https://doi.org/10.1371/journal.pone.0138189 (2015).Pineault, K. M. et al. Hox11 genes regulate postnatal longitudinal bone growth and growth plate proliferation. Biol. Open 4, 1538–1548 (2015).CAS

PubMed

PubMed Central

Google Scholar

Yu, V. W. C. et al. FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice. J. Cell Biol. 169, 591–601 (2005).CAS

PubMed

PubMed Central

Google Scholar

Ambrogini, E. et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 11, 136–146 (2010).CAS

PubMed

PubMed Central

Google Scholar

Shimoyama, A. et al. Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol. Biol. Cell 18, 2411–2418 (2007).CAS

PubMed

PubMed Central

Google Scholar

Li, J. et al. Suppressor of fused restraint of hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development. J. Biol. Chem. 292, 15814–15825 (2017).CAS

PubMed

PubMed Central

Google Scholar

Funato, N. et al. Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development 136, 615–625 (2009).CAS

PubMed

Google Scholar

Kanzler, B., Kuschert, S. J., Liu, Y. H. & Mallo, M. Hoxa-2 restricts the chondrogenic domain and inhibits bone formation during development of the branchial area. Development 125, 2587–2597 (1998).CAS

PubMed

Google Scholar

Komori, T. Regulation of osteoblast differentiation by runx2. Adv. Exp. Med. Biol. 658, 43–49 (2010).CAS

PubMed

Google Scholar

Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).CAS

PubMed

Google Scholar

Bialek, P. et al. A twist code determines the onset of osteoblast differentiation. Dev. Cell 6, 423–435 (2004).CAS

PubMed

Google Scholar

Cancela, L., Hsieh, C. L. & Francke, U. P. P. Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene. J. Biol. Chem. 265, 15040–15048 (1990).CAS

PubMed

Google Scholar

Karsenty, G. & Park, R. W. Regulation of type I collagen genes expression. Int. Rev. Immunol. 12, 177–185 (1995).CAS

PubMed

Google Scholar

Pinzone, J. J. et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113, 517–525 (2009).CAS

PubMed

PubMed Central

Google Scholar

Kim, J. B. et al. Reconciling the roles of FAK in osteoblast differentiation, osteoclast remodeling, and bone regeneration. Bone 41, 39–51 (2007).CAS

PubMed

PubMed Central

Google Scholar

Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).CAS

PubMed

Google Scholar

Download referencesAuthor informationAuthor notesThese authors contributed equally: Ankit Salhotra, Harsh N. Shah.Authors and AffiliationsDivision of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USAAnkit Salhotra, Harsh N. Shah & Michael T. LongakerInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USAAnkit Salhotra, Harsh N. Shah & Michael T. LongakerDepartment of Surgery, University of Michigan, Ann Arbor, MI, USABenjamin LeviAuthorsAnkit SalhotraView author publicationsYou can also search for this author in

PubMed Google ScholarHarsh N. ShahView author publicationsYou can also search for this author in

PubMed Google ScholarBenjamin LeviView author publicationsYou can also search for this author in

PubMed Google ScholarMichael T. LongakerView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsThe authors contributed equally to all aspects of the article.Corresponding authorsCorrespondence to

Benjamin Levi or Michael T. Longaker.Ethics declarations

Competing interests

The authors declare no competing interests.

Additional informationPeer review informationNature Reviews Molecular Cell Biology thanks Noriaki Ono and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.GlossaryOsteon

A cylindrical structure consisting of a mineralized matrix and osteocytes that transports blood through connected canaliculi.

Long bone growth plate

An area of differentiating tissue located near the ends of long bones that enables physiological lengthening of the bones.

Axial skeleton

The portion of the skeleton consisting of the bones of the head and vertebrae.

Appendicular skeleton

The portion of the skeleton consisting of the bones of the appendages.

Cancellous bone

Mature adult bone consisting of spongy tissue meshwork typically found in the cores of vertebral bones and the ends of long bones.

Unicortical defect

A fracture involving only the outer and/or inner cortices on one side of the bone shaft.

Rights and permissionsReprints and permissionsAbout this articleCite this articleSalhotra, A., Shah, H.N., Levi, B. et al. Mechanisms of bone development and repair.

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6.3 Bone Structure – Anatomy & Physiology

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Contents

Chapter 1. An Introduction to the Human Body1.0 Introduction1.1 How Structure Determines Function1.2 Structural Organization of the Human Body1.3 Homeostasis1.4 Anatomical Terminology1.5 Medical ImagingChapter 2. The Chemical Level of Organization2.0 Introduction2.1 Elements and Atoms: The Building Blocks of Matter2.2 Chemical Bonds2.3 Chemical Reactions2.4 Inorganic Compounds Essential to Human Functioning2.5 Organic Compounds Essential to Human FunctioningChapter 3. The Cellular Level of Organization3.0 Introduction3.1 The Cell Membrane3.2 The Cytoplasm and Cellular Organelles3.3 The Nucleus and DNA Replication3.4 Protein Synthesis3.5 Cell Growth and Division3.6 Cellular DifferentiationChapter 4. The Tissue Level of Organization4.0 Introduction4.1 Types of Tissues4.2 Epithelial Tissue4.3 Connective Tissue Supports and Protects4.4 Muscle Tissue4.5 Nervous Tissue4.6 Tissue Injury and AgingChapter 5. The Integumentary System5.0 Introduction5.1 Layers of the Skin5.2 Accessory Structures of the Skin5.3 Functions of the Integumentary System5.4 Diseases, Disorders, and Injuries of the Integumentary SystemChapter 6. Bone Tissue and the Skeletal System6.0 Introduction6.1 The Functions of the Skeletal System6.2 Bone Classification6.3 Bone Structure6.4 Bone Formation and Development6.5 Fractures: Bone Repair6.6 Exercise, Nutrition, Hormones, and Bone Tissue6.7 Calcium Homeostasis: Interactions of the Skeletal System and Other Organ SystemsChapter 7. Axial Skeleton7.0 Introduction7.1 Divisions of the Skeletal System7.2 Bone Markings7.3 The Skull7.4 The Vertebral Column7.5 The Thoracic Cage7.6 Embryonic Development of the Axial SkeletonChapter 8. The Appendicular Skeleton8.0 Introduction8.1 The Pectoral Girdle8.2 Bones of the Upper Limb8.3 The Pelvic Girdle and Pelvis8.4 Bones of the Lower Limb8.5 Development of the Appendicular SkeletonChapter 9. Joints9.0 Introduction9.1 Classification of Joints9.2 Fibrous Joints9.3 Cartilaginous Joints9.4 Synovial Joints9.5 Types of Body Movements9.6 Anatomy of Selected Synovial Joints9.7 Development of JointsChapter 10. Muscle Tissue10.0 Introduction10.1 Overview of Muscle Tissues10.2 Skeletal Muscle10.3 Muscle Fiber Excitation, Contraction, and Relaxation10.4 Nervous System Control of Muscle Tension10.5 Types of Muscle Fibers10.6 Exercise and Muscle Performance10.7 Smooth Muscle Tissue10.8 Development and Regeneration of Muscle TissueChapter 11. The Muscular System11.0 Introduction11.1 Describe the roles of agonists, antagonists and synergists11.2 Explain the organization of muscle fascicles and their role in generating force11.3 Explain the criteria used to name skeletal muscles11.4 Axial Muscles of the Head Neck and Back11.5 Axial muscles of the abdominal wall and thorax11.6 Muscles of the Pectoral Girdle and Upper Limbs11.7 Appendicular Muscles of the Pelvic Girdle and Lower LimbsChapter 12. The Nervous System and Nervous Tissue12.0 Introduction12.1 Structure and Function of the Nervous System12.2 Nervous Tissue12.3 The Function of Nervous Tissue12.4 Communication Between Neurons12.5 The Action PotentialChapter 13. The Peripheral Nervous System13.0 Introduction13.1 Sensory Receptors13.2 Ganglia and Nerves13.3 Spinal and Cranial Nerves13.4 Relationship of the PNS to the Spinal Cord of the CNS13.5 Ventral Horn Output and Reflexes13.6 Testing the Spinal Nerves (Sensory and Motor Exams)13.7 The Cranial Nerve ExamChapter 14. The Central Nervous System14.0 Introduction14.1 Embryonic Development14.2 Blood Flow the meninges and Cerebrospinal Fluid Production and Circulation14.3 The Brain and Spinal Cord14.4 The Spinal Cord14.5 Sensory and Motor PathwaysChapter 15. The Special Senses15.0 Introduction15.1 Taste15.2 Smell15.3 Hearing15.4 Equilibrium15.5 VisionChapter 16. The Autonomic Nervous System16.0 Introduction16.1 Divisions of the Autonomic Nervous System16.2 Autonomic Reflexes and Homeostasis16.3 Central Control16.4 Drugs that Affect the Autonomic SystemChapter 17. The Endocrine System17.0 Introduction17.1 An Overview of the Endocrine System17.2 Hormones17.3 The Pituitary Gland and Hypothalamus17.4 The Thyroid Gland17.5 The Parathyroid Glands17.6 The Adrenal Glands17.7 The Pineal Gland17.8 Gonadal and Placental Hormones17.9 The Pancreas17.10 Organs with Secondary Endocrine Functions17.11 Development and Aging of the Endocrine SystemChapter 18. The Cardiovascular System: Blood18.0 Introduction18.1 Functions of Blood18.2 Production of the Formed Elements18.3 Erythrocytes18.4 Leukocytes and Platelets18.5 Hemostasis18.6 Blood TypingChapter 19. The Cardiovascular System: The Heart19.0 Introduction19.1 Heart Anatomy19.2 Cardiac Muscle and Electrical Activity19.3 Cardiac Cycle19.4 Cardiac Physiology19.5 Development of the HeartChapter 20. The Cardiovascular System: Blood Vessels and Circulation20.0 Introduction20.1 Structure and Function of Blood Vessels20.2 Blood Flow, Blood Pressure, and Resistance20.3 Capillary Exchange20.4 Homeostatic Regulation of the Vascular System20.5 Circulatory Pathways20.6 Development of Blood Vessels and Fetal CirculationChapter 21. The Lymphatic and Immune System21.0 Introduction21.1 Anatomy of the Lymphatic and Immune Systems21.2 Barrier Defenses and the Innate Immune Response21.3 The Adaptive Immune Response: T lymphocytes and Their Functional Types21.4 The Adaptive Immune Response: B-lymphocytes and Antibodies21.5 The Immune Response against Pathogens21.6 Diseases Associated with Depressed or Overactive Immune Responses21.7 Transplantation and Cancer ImmunologyChapter 22. The Respiratory System22.0 Introduction22.1 Organs and Structures of the Respiratory System22.2 The Lungs22.3 The Process of Breathing22.4 Gas Exchange22.5 Transport of Gases22.6 Modifications in Respiratory Functions22.7 Embryonic Development of the Respiratory SystemChapter 23. The Digestive System23.0 Introduction23.1 Overview of the Digestive System23.2 Digestive System Processes and Regulation23.3 The Mouth, Pharynx, and Esophagus23.4 The Stomach23.5 Accessory Organs in Digestion: The Liver, Pancreas, and Gallbladder23.6 The Small and Large Intestines23.7 Chemical Digestion and Absorption: A Closer LookChapter 24. Metabolism and Nutrition24.0 Introduction24.1 Overview of Metabolic Reactions24.2 Carbohydrate Metabolism24.3 Lipid Metabolism24.4 Protein Metabolism24.5 Metabolic States of the Body24.6 Energy and Heat Balance24.7 Nutrition and DietChapter 25. The Urinary System25.0 Introduction25.1 Internal and External Anatomy of the Kidney25.2 Microscopic Anatomy of the Kidney: Anatomy of the Nephron25.3 Physiology of Urine Formation: Overview25.4 Physiology of Urine Formation: Glomerular Filtration25.5 Physiology of Urine Formation: Tubular Reabsorption and Secretion25.6 Physiology of Urine Formation: Medullary Concentration Gradient25.7 Physiology of Urine Formation: Regulation of Fluid Volume and Composition25.8 Urine Transport and Elimination25.9 The Urinary System and HomeostasisChapter 26. Fluid, Electrolyte, and Acid-Base Balance26.0 Introduction26.1 Body Fluids and Fluid Compartments26.2 Water Balance26.3 Electrolyte Balance26.4 Acid-Base Balance26.5 Disorders of Acid-Base BalanceChapter 27. The Sexual Systems27.0 Introduction27.1 Anatomy of Sexual Systems27.2 Development of Sexual Anatomy27.3 Physiology of the Female Sexual System27.4 Physiology of the Male Sexual System27.5 Physiology of Arousal and OrgasmChapter 28. Development and Inheritance28.0 Introduction28.1 Fertilization28.2 Embryonic Development28.3 Fetal Development28.4 Maternal Changes During Pregnancy, Labor, and Birth28.5 Adjustments of the Infant at Birth and Postnatal Stages28.6 Lactation28.7 Patterns of Inheritance Creative Commons LicenseRecommended CitationsVersioning

Anatomy & Physiology

6.3 Bone Structure

Learning Objectives

By the end of this section, you will be able to:

Describe the microscopic and gross anatomical structures of bones

Identify the gross anatomical features of a bone

Describe the histology of bone tissue, including the function of bone cells and matrix

Compare and contrast compact and spongy bone

Identify the structures that compose compact and spongy bone

Describe how bones are nourished and innervated

function?

Bone tissue (osseous tissue) differs greatly from other tissues in the body. Bone is hard and many of its functions depend on that characteristic hardness. Later discussions in this chapter will show that bone is also dynamic in that its shape adjusts to accommodate stresses. This section will examine the gross anatomy of bone first and then move on to its histology.

Gross Anatomy of Bones

A long bone has two main regions: the diaphysis and the epiphysis (Figure 6.3.1). The diaphysis is the hollow, tubular shaft that runs between the proximal and distal ends of the bone. Inside the diaphysis is the medullary cavity, which is filled with yellow bone marrow in an adult. The outer walls of the diaphysis (cortex, cortical bone) are composed of dense and hard compact bone, a form of osseous tissue.

Figure 6.3.1 – Anatomy of a Long Bone: A typical long bone showing gross anatomical features.

The wider section at each end of the bone is called the epiphysis (plural = epiphyses), which is filled internally with spongy bone, another type of osseous tissue. Red bone marrow fills the spaces between the spongy bone in some long bones. Each epiphysis meets the diaphysis at the metaphysis. During growth, the metaphysis contains the epiphyseal plate, the site of long bone elongation described later in the chapter. When the bone stops growing in early adulthood (approximately 18–21 years), the epiphyseal plate becomes an epiphyseal line seen in the figure.

Lining the inside of the bone adjacent to the medullary cavity is a layer of bone cells called the endosteum (endo- = “inside”; osteo- = “bone”). These bone cells (described later) cause the bone to grow, repair, and remodel throughout life. On the outside of bones there is another layer of cells that grow, repair and remodel bone as well. These cells are part of the outer double layered structure called the periosteum (peri– = “around” or “surrounding”). The cellular layer is adjacent to the cortical bone and is covered by an outer fibrous layer of dense irregular connective tissue (see Figure 6.3.4a). The periosteum also contains blood vessels, nerves, and lymphatic vessels that nourish compact bone. Tendons and ligaments attach to bones at the periosteum. The periosteum covers the entire outer surface except where the epiphyses meet other bones to form joints (Figure 6.3.2). In this region, the epiphyses are covered with articular cartilage, a thin layer of hyaline cartilage that reduces friction and acts as a shock absorber.

Figure 6.32 – Periosteum and Endosteum: The periosteum forms the outer surface of bone, and the endosteum lines the medullary cavity.

Flat bones, like those of the cranium, consist of a layer of diploë (spongy bone), covered on either side by a layer of compact bone (Figure 6.3.3). The two layers of compact bone and the interior spongy bone work together to protect the internal organs. If the outer layer of a cranial bone fractures, the brain is still protected by the intact inner layer.

Figure 6.3.3 – Anatomy of a Flat Bone: This cross-section of a flat bone shows the spongy bone (diploë) covered on either side by a layer of compact bone.

Osseous Tissue: Bone Matrix and Cells

Bone Matrix

Osseous tissue is a connective tissue and like all connective tissues contains relatively few cells and large amounts of extracellular matrix. By mass, osseous tissue matrix consists of 1/3rd collagen fibers and 2/3rds calcium phosphate salt. The collagen provides a scaffolding surface for inorganic salt crystals to adhere (see Figure 6.3.4a). These salt crystals form when calcium phosphate and calcium carbonate combine to create hydroxyapatite. Hydroxyapatite also incorporates other inorganic salts like magnesium hydroxide, fluoride, and sulfate as it crystallizes, or calcifies, on the collagen fibers. The hydroxyapatite crystals give bones their hardness and strength, while the collagen fibers give them a framework for calcification and gives the bone flexibility so that it can bend without being brittle. For example, if you removed all the organic matrix (collagen) from a bone, it would crumble and shatter readily (see Figure 6.3.4b, upper panel). Conversely, if you remove all the inorganic matrix (minerals) from bone and leave the collagen, the bone becomes overly flexible and cannot bear weight (see Figure 6.3.4b, lower panel).

Figure 6.3.4a Calcified collagen fibers from bone (scanning electron micrograph, 10,000 X, By Sbertazzo – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20904735)

Figure 6.3.4b Contributions of the organic and inorganic matrices of bone. Image from Ammerman figure 6-5, Pearson

Bone Cells

Although bone cells compose less than 2% of the bone mass, they are crucial to the function of bones. Four types of cells are found within bone tissue: osteoblasts, osteocytes, osteogenic cells, and osteoclasts (Figure 6.3.5).

Figure 6.3.5 – Bone Cells: Four types of cells are found within bone tissue. Osteogenic cells are undifferentiated and develop into osteoblasts. Osteoblasts deposit bone matrix. When osteoblasts get trapped within the calcified matrix, they become osteocytes. Osteoclasts develop from a different cell lineage and act to resorb bone.

The osteoblast is the bone cell responsible for forming new bone and is found in the growing portions of bone, including the endosteum and the cellular layer of the periosteum. Osteoblasts, which do not divide, synthesize and secrete the collagen matrix and other proteins. As the secreted matrix surrounding the osteoblast calcifies, the osteoblast become trapped within it; as a result, it changes in structure and becomes an osteocyte, the primary cell of mature bone and the most common type of bone cell. Each osteocyte is located in a small cavity in the bone tissue called a lacuna (lacunae for plural). Osteocytes maintain the mineral concentration of the matrix via the secretion of enzymes. Like osteoblasts, osteocytes lack mitotic activity. They can communicate with each other and receive nutrients via long cytoplasmic processes that extend through canaliculi (singular = canaliculus), channels within the bone matrix. Osteocytes are connected to one another within the canaliculi via gap junctions.

If osteoblasts and osteocytes are incapable of mitosis, then how are they replenished when old ones die? The answer lies in the properties of a third category of bone cells—the osteogenic (osteoprogenitor) cell. These osteogenic cells are undifferentiated with high mitotic activity and they are the only bone cells that divide. Immature osteogenic cells are found in the cellular layer of the periosteum and the endosteum. They differentiate and develop into osteoblasts.

The dynamic nature of bone means that new tissue is constantly formed, and old, injured, or unnecessary bone is dissolved for repair or for calcium release. The cells responsible for bone resorption, or breakdown, are the osteoclasts. These multinucleated cells originate from monocytes and macrophages, two types of white blood cells, not from osteogenic cells. Osteoclasts are continually breaking down old bone while osteoblasts are continually forming new bone. The ongoing balance between osteoblasts and osteoclasts is responsible for the constant but subtle reshaping of bone. Table 6.3 reviews the bone cells, their functions, and locations.

Bone Cells (Table 6.3)

Cell type

Function

Location

Osteogenic cells

Develop into osteoblasts

Endosteum, cellular layer of the periosteum

Osteoblasts

Bone formation

Endosteum, cellular layer of the periosteum, growing portions of bone

Osteocytes

Maintain mineral concentration of matrix

Entrapped in matrix

Osteoclasts

Bone resorption

Endosteum, cellular layer of the periosteum, at sites of old, injured, or unneeded bone

Compact and Spongy Bone

Most bones contain compact and spongy osseous tissue, but their distribution and concentration vary based on the bone’s overall function. Although compact and spongy bone are made of the same matrix materials and cells, they are different in how they are organized. Compact bone is dense so that it can withstand compressive forces, while spongy bone (also called cancellous bone) has open spaces and is supportive, but also lightweight and can be readily remodeled to accommodate changing body needs.

Compact Bone

Compact bone is the denser, stronger of the two types of osseous tissue (Figure 6.3.6). It makes up the outer cortex of all bones and is in immediate contact with the periosteum. In long bones, as you move from the outer cortical compact bone to the inner medullary cavity, the bone transitions to spongy bone.

Figure 6.3.6 – Diagram of Compact Bone: (a) This cross-sectional view of compact bone shows several osteons, the basic structural unit of compact bone. (b) In this micrograph of the osteon, you can see the concentric lamellae around the central canals. LM × 40. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Figure 6.3.7 Osteon

If you look at compact bone under the microscope, you will observe a highly organized arrangement of concentric circles that look like tree trunks. Each group of concentric circles (each “tree”) makes up the microscopic structural unit of compact bone called an osteon (this is also called a Haversian system). Each ring of the osteon is made of collagen and calcified matrix and is called a lamella (plural = lamellae). The collagen fibers of adjacent lamallae run at perpendicular angles to each other, allowing osteons to resist twisting forces in multiple directions (see figure 6.34a). Running down the center of each osteon is the central canal, or Haversian canal, which contains blood vessels, nerves, and lymphatic vessels. These vessels and nerves branch off at right angles through a perforating canal, also known as Volkmann’s canals, to extend to the periosteum and endosteum. The endosteum also lines each central canal, allowing osteons to be removed, remodeled and rebuilt over time.

The osteocytes are trapped within their lacuane, found at the borders of adjacent lamellae. As described earlier, canaliculi connect with the canaliculi of other lacunae and eventually with the central canal. This system allows nutrients to be transported to the osteocytes and wastes to be removed from them despite the impervious calcified matrix.

Spongy (Cancellous) Bone

Like compact bone, spongy bone, also known as cancellous bone, contains osteocytes housed in lacunae, but they are not arranged in concentric circles. Instead, the lacunae and osteocytes are found in a lattice-like network of matrix spikes called trabeculae (singular = trabecula) (Figure 6.3.8). The trabeculae are covered by the endosteum, which can readily remodel them. The trabeculae may appear to be a random network, but each trabecula forms along lines of stress to direct forces out to the more solid compact bone providing strength to the bone. Spongy bone provides balance to the dense and heavy compact bone by making bones lighter so that muscles can move them more easily. In addition, the spaces in some spongy bones contain red bone marrow, protected by the trabeculae, where hematopoiesis occurs.

Figure 6.3.8 – Diagram of Spongy Bone: Spongy bone is composed of trabeculae that contain the osteocytes. Red marrow fills the spaces in some bones.

Aging and the…Skeletal System: Paget’s Disease

Paget’s disease usually occurs in adults over age 40. It is a disorder of the bone remodeling process that begins with overactive osteoclasts. This means more bone is resorbed than is laid down. The osteoblasts try to compensate but the new bone they lay down is weak and brittle and therefore prone to fracture.

While some people with Paget’s disease have no symptoms, others experience pain, bone fractures, and bone deformities (Figure 6.3.9). Bones of the pelvis, skull, spine, and legs are the most commonly affected. When occurring in the skull, Paget’s disease can cause headaches and hearing loss.

Figure 6.3.9 – Paget’s Disease: Normal leg bones are relatively straight, but those affected by Paget’s disease are porous and curved.

What causes the osteoclasts to become overactive? The answer is still unknown, but hereditary factors seem to play a role. Some scientists believe Paget’s disease is due to an as-yet-unidentified virus.

Paget’s disease is diagnosed via imaging studies and lab tests. X-rays may show bone deformities or areas of bone resorption. Bone scans are also useful. In these studies, a dye containing a radioactive ion is injected into the body. Areas of bone resorption have an affinity for the ion, so they will light up on the scan if the ions are absorbed. In addition, blood levels of an enzyme called alkaline phosphatase are typically elevated in people with Paget’s disease. Bisphosphonates, drugs that decrease the activity of osteoclasts, are often used in the treatment of Paget’s disease.

Blood and Nerve Supply

The spongy bone and medullary cavity receive nourishment from arteries that pass through the compact bone. The arteries enter through the nutrient foramen (plural = foramina), small openings in the diaphysis (Figure 6.3.10). The osteocytes in spongy bone are nourished by blood vessels of the periosteum that penetrate spongy bone and blood that circulates in the marrow cavities. As the blood passes through the marrow cavities, it is collected by veins, which then pass out of the bone through the foramina.

In addition to the blood vessels, nerves follow the same paths into the bone where they tend to concentrate in the more metabolically active regions of the bone. The nerves sense pain, and it appears the nerves also play roles in regulating blood supplies and in bone growth, hence their concentrations in metabolically active sites of the bone.

Figure 6.3.10 – Diagram of Blood and Nerve Supply to Bone: Blood vessels and nerves enter the bone through the nutrient foramen.

External Website

Watch this video to see the microscopic features of a bone.

Chapter Review

A hollow medullary cavity filled with yellow marrow runs the length of the diaphysis of a long bone. The walls of the diaphysis are compact bone. The epiphyses, which are wider sections at each end of a long bone, are filled with spongy bone and red marrow. The epiphyseal plate, a layer of hyaline cartilage, is replaced by osseous tissue as the organ grows in length. The medullary cavity has a delicate membranous lining called the endosteum. The outer surface of bone, except in regions covered with articular cartilage, is covered with a fibrous membrane called the periosteum. Flat bones consist of two layers of compact bone surrounding a layer of spongy bone. Bone markings depend on the function and location of bones. Articulations are places where two bones meet. Projections stick out from the surface of the bone and provide attachment points for tendons and ligaments. Holes are openings or depressions in the bones.

Bone matrix consists of collagen fibers and organic ground substance, primarily hydroxyapatite formed from calcium salts. Osteogenic cells develop into osteoblasts. Osteoblasts are cells that make new bone. They become osteocytes, the cells of mature bone, when they get trapped in the matrix. Osteoclasts engage in bone resorption. Compact bone is dense and composed of osteons, while spongy bone is less dense and made up of trabeculae. Blood vessels and nerves enter the bone through the nutrient foramina to nourish and innervate bones.

Review Questions

Critical Thinking Questions

1. If the articular cartilage at the end of one of your long bones were to degenerate, what symptoms do you think you would experience? Why?

2. In what ways is the structural makeup of compact and spongy bone well suited to their respective functions?

Glossary

articular cartilage

thin layer of cartilage covering an epiphysis; reduces friction and acts as a shock absorber

articulation

where two bone surfaces meet

canaliculi

(singular = canaliculus) channels within the bone matrix that house one of an osteocyte’s many cytoplasmic extensions that it uses to communicate and receive nutrients

central canal

longitudinal channel in the center of each osteon; contains blood vessels, nerves, and lymphatic vessels; also known as the Haversian canal

compact bone

dense osseous tissue that can withstand compressive forces

diaphysis

tubular shaft that runs between the proximal and distal ends of a long bone

diploë

layer of spongy bone, that is sandwiched between two the layers of compact bone found in flat bones

endosteum

delicate membranous lining of a bone’s medullary cavity

epiphyseal plate

(also, growth plate) sheet of hyaline cartilage in the metaphysis of an immature bone; replaced by bone tissue as the organ grows in length

epiphysis

wide section at each end of a long bone; filled with spongy bone and red marrow

hole

opening or depression in a bone

lacunae

(singular = lacuna) spaces in a bone that house an osteocyte

medullary cavity

hollow region of the diaphysis; filled with yellow marrow

nutrient foramen

small opening in the middle of the external surface of the diaphysis, through which an artery enters the bone to provide nourishment

osteoblast

cell responsible for forming new bone

osteoclast

cell responsible for resorbing bone

osteocyte

primary cell in mature bone; responsible for maintaining the matrix

osteogenic cell

undifferentiated cell with high mitotic activity; the only bone cells that divide; they differentiate and develop into osteoblasts

osteon

(also, Haversian system) basic structural unit of compact bone; made of concentric layers of calcified matrix

perforating canal

(also, Volkmann’s canal) channel that branches off from the central canal and houses vessels and nerves that extend to the periosteum and endosteum

periosteum

fibrous membrane covering the outer surface of bone and continuous with ligaments

projection

bone markings where part of the surface sticks out above the rest of the surface, where tendons and ligaments attach

spongy bone

(also, cancellous bone) trabeculated osseous tissue that supports shifts in weight distribution

trabeculae

(singular = trabecula) spikes or sections of the lattice-like matrix in spongy bone

Solutions

Answers for Critical Thinking Questions

If the articular cartilage at the end of one of your long bones were to deteriorate, which is actually what happens in osteoarthritis, you would experience joint pain at the end of that bone and limitation of motion at that joint because there would be no cartilage to reduce friction between adjacent bones and there would be no cartilage to act as a shock absorber.

The densely packed concentric rings of matrix in compact bone are ideal for resisting compressive forces, which is the function of compact bone. The open spaces of the trabeculated network of spongy bone allow spongy bone to support shifts in weight distribution, which is the function of spongy bone.

Bone Markings

Define and list examples of bone markings

The surface features of bones vary considerably, depending on the function and location in the body. Table 6.2 describes the bone markings, which are illustrated in (Figure 6.3.4). There are three general classes of bone markings: (1) articulations, (2) projections, and (3) holes. As the name implies, an articulation is where two bone surfaces come together (articulus = “joint”). These surfaces tend to conform to one another, such as one being rounded and the other cupped, to facilitate the function of the articulation. A projection is an area of a bone that projects above the surface of the bone. These are the attachment points for tendons and ligaments. In general, their size and shape is an indication of the forces exerted through the attachment to the bone. A hole is an opening or groove in the bone that allows blood vessels and nerves to enter the bone. As with the other markings, their size and shape reflect the size of the vessels and nerves that penetrate the bone at these points.

Bone Markings (Table 6.2)

Marking

Description

Example

Articulations

Where two bones meet

Knee joint

Head

Prominent rounded surface

Head of femur

Facet

Flat surface

Vertebrae

Condyle

Rounded surface

Occipital condyles

Projections

Raised markings

Spinous process of the vertebrae

Protuberance

Protruding

Chin

Process

Prominence feature

Transverse process of vertebra

Spine

Sharp process

Ischial spine

Tubercle

Small, rounded process

Tubercle of humerus

Tuberosity

Rough surface

Deltoid tuberosity

Line

Slight, elongated ridge

Temporal lines of the parietal bones

Crest

Ridge

Iliac crest

Holes

Holes and depressions

Foramen (holes through which blood vessels can pass through)

Fossa

Elongated basin

Mandibular fossa

Fovea

Small pit

Fovea capitis on the head of the femur

Sulcus

Groove

Sigmoid sulcus of the temporal bones

Canal

Passage in bone

Auditory canal

Fissure

Slit through bone

Auricular fissure

Foramen

Hole through bone

Foramen magnum in the occipital bone

Meatus

Opening into canal

External auditory meatus

Sinus

Air-filled space in bone

Nasal sinus

Figure 6.3.4 Bone Features The surface features of bones depend on their function, location, attachment of ligaments and tendons, or the penetration of blood vessels and nerves.

This work, Anatomy & Physiology, is adapted from Anatomy & Physiology by OpenStax, licensed under CC BY. This edition, with revised content and artwork, is licensed under CC BY-SA except where otherwise noted.

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Anatomy & Physiology Copyright © 2019 by Lindsay M. Biga, Staci Bronson, Sierra Dawson, Amy Harwell, Robin Hopkins, Joel Kaufmann, Mike LeMaster, Philip Matern, Katie Morrison-Graham, Kristen Oja, Devon Quick, Jon Runyeon, OSU OERU, and OpenStax is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License, except where otherwise noted.

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The Computational Mechanics of Bone Tissue pp 3–43Cite as

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The Computational Mechanics of Bone Tissue

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Bone: Functions, Structure and Physiology

Joana da Costa Reis6 & Maria Teresa Oliveira6

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First Online: 12 February 2020

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Part of the Lecture Notes in Computational Vision and Biomechanics book series (LNCVB,volume 35)

AbstractIn this chapter, bone functions, regulation,

morphological structure and physiology are revisited. Bone is a highly complex tissue, very sensitive and responsive to external and internal stimuli, and intimately intertwined with other organs. From embryogenesis to endocrine regulation and bone remodelling, a global assessment is presented. Considering the scope of this book, special emphasis is given to how cell structure and tissue organization modulate the response to mechanical stimuli.Joana da Costa Reis and Maria Teresa Oliveira contributed equally to this work.

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Referencesde Vries WN, Evsikov AV, Haak BE et al (2004) Maternal β-catenin and E-cadherin in mouse development. Development 131:4435–4445Article

PubMed

CAS

Google Scholar

Ingber DE (2006) Mechanical control of tissue morphogenesis during embryological development. Dev Biol 50:255–266

Google Scholar

Oster GF, Murray JD, Harris AK (1983) Mechanical aspects of mesenchymal morphogenesis. J Embryol Exp Morphol 78:83–125CAS

PubMed

Google Scholar

Takeichi M (1988) The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development 102:639–655CAS

PubMed

Google Scholar

Tang Z, Hu Y, Wang Z et al (2018) Mechanical forces program the orientation of cell division during airway tube morphogenesis. Dev Cell 44:313–325Article

CAS

PubMed

Google Scholar

Foubet O, Trejo M, Toro R (2018) Mechanical morphogenesis and the development of neocortical organisation. Cortex

Google Scholar

Cartwright JHE, Piro O, Tuval I (2004) Fluid-dynamical basis of the embryonic development of left-right asymmetry in vertebrates. Proc Natl Acad Sci USA 101:7234–7239Article

CAS

Google Scholar

Collignon J, Varlet I, Robertson EJ (1996) Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381:155–158Article

CAS

PubMed

Google Scholar

Nakamura T, Mine N, Nakaguchi E et al (2006) Generation of robust left-right asymmetry in the mouse embryo requires a self-enhancement and lateral-inhibition system. Dev Cell 11:495–504Article

CAS

PubMed

Google Scholar

Okada Y, Nonaka S, Tanaka Y et al (1999) Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 4:459–468Article

CAS

PubMed

Google Scholar

McGrath J, Somlo S, Makova S et al (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61–73Article

CAS

PubMed

Google Scholar

Patwari P, Lee RT (2008) Mechanical control of tissue morphogenesis. Circ Res 103:234–243Article

CAS

PubMed

PubMed Central

Google Scholar

Schmidt A, Brixius K, Bloch W (2007) Endothelial precursor cell migration during vasculogenesis. Circ Res 101:125–136Article

CAS

PubMed

Google Scholar

Anava S, Greenbaum A, Ben Jacob E et al (2009) The regulative role of neurite mechanical tension in network development. Biophys J 96:1661–1670Article

CAS

PubMed

PubMed Central

Google Scholar

Bray D (1979) Mechanical tension produced by nerve cells in tissue culture. J Cell Sci 37:391–410CAS

PubMed

Google Scholar

Dennerll TJ, Lamoureux P, Buxbaum RE, Heidemann SR (1989) The cytomechanics of axonal elongation and retraction. J Cell Biol 109:3073–3083Article

CAS

PubMed

Google Scholar

le Noble F, Klein C, Tintu A et al (2008) Neural guidance molecules, tip cells, and mechanical factors in vascular development. Cardiovasc Res 78:232–241Article

PubMed

CAS

Google Scholar

Carter DR, Beaupré GS (2001) Skeletal tissue histomorphology and mechanics. Skeletal function and form. Cambridge University Press, Cambridge, pp 31–52

Google Scholar

Belanger LF (1969) Osteocytic osteolysis. Calcif Tissue Res 4:1–12Article

CAS

PubMed

Google Scholar

Teti A, Zallone A (2009) Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 44:11–16Article

CAS

PubMed

Google Scholar

Zallone A, Teti A, Primavera MV, Pace G (1983) Mature osteocytes behaviour in a repletion period: the occurrence of osteoplastic activity. Basic Appl Histochem 27:191–204

Google Scholar

Green J, Kleeman CR (1991) The role of bone in the regulation of systemic acid-base balance. Kidney Int 39:9–26Article

CAS

PubMed

Google Scholar

Arnett T (2003) Regulation of bone cell function by acid-base balance. Proc Nutr Soc 62:511–520Article

CAS

PubMed

Google Scholar

Bushinsky DA, Krieger NS (2015) Acid-base balance and bone health. In: Holick MF, JNieves NW (eds) Nutrition and bone health. Humana Press Springer, New York, pp 335–357

Google Scholar

Baylink DJ, Finkelman RD, Mohan S (1993) Growth factors to stimulate bone formation. J Bone Miner Res 8:S565–S572Article

PubMed

Google Scholar

Linkhart TA, Mohan S, Baylink DJ (1996) Growth factors for bone growth and repair: IGF, TGFβ and BMP. Bone 19:S1–S12Article

Google Scholar

Krings A, Rahman S, Huang S et al (2012) Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone 50:546–552Article

CAS

PubMed

Google Scholar

Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM (2009) Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 19:109–124Article

CAS

PubMed

PubMed Central

Google Scholar

Suchacki KJ, Cawthorn WP, Rosen CJ (2016) Bone marrow adipose tissue: formation, function and regulation. Curr Opin Pharmacol 28:50–56Article

CAS

PubMed

PubMed Central

Google Scholar

Roelofs-Iverson RA, Mulder DW, Elveback LR et al (1984) ALS and heavy metals: a pilot case-control study. Neurology 34:393Article

CAS

PubMed

Google Scholar

Sharma B, Singh S, Siddiqi NJ (2014) Biomedical implications of heavy metals induced imbalances in redox systems. BioMed Research Int 2014:640754

Google Scholar

Rhee Y, Bivi N, Farrow E et al (2011) Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49:636–643Article

CAS

PubMed

PubMed Central

Google Scholar

Yamashita T, Yoshioka M, Itoh N (2000) Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277:494–498Article

CAS

PubMed

Google Scholar

Masuyama R, Stockmans I, Torrekens S et al (2006) Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest 116:3150–3159Article

CAS

PubMed

PubMed Central

Google Scholar

Fukumoto S, Martin TJ (2009) Bone as an endocrine organ. Trends Endocrinol Metab 20:230–236Article

CAS

PubMed

Google Scholar

Haussler MR, Whitfield GK, Kaneko I et al (2012) The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord 13:57–69Article

CAS

PubMed

PubMed Central

Google Scholar

Shimada T, Hasegawa H, Yamazaki Y et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435Article

CAS

PubMed

Google Scholar

David V, Dai B, Martin A et al (2013) Calcium regulates FGF-23 expression in bone. Endocrinology 154:4469–4482Article

CAS

PubMed

PubMed Central

Google Scholar

Rodriguez-Ortiz ME, Lopez I, Muñoz-Castañeda JR et al (2012) Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 23:1190–1197Article

CAS

PubMed

PubMed Central

Google Scholar

Fukumoto S, Yamashita T (2007) FGF23 is a hormone-regulating phosphate metabolism-unique biological characteristics of FGF23. Bone 40:1190–1195Article

CAS

PubMed

Google Scholar

ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348Article

CAS

Google Scholar

Shimada T, Mizutani S, Muto T et al (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98:6500–6505Article

CAS

Google Scholar

Lyles KW, Halsey DL, Friedman NE, Lobaugh B (1988) Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis. J Clin Endocrinol Metab 67:88–92Article

CAS

PubMed

Google Scholar

Urakawa I, Yamazaki Y, Shimada T et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774Article

CAS

PubMed

Google Scholar

Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833Article

CAS

PubMed

PubMed Central

Google Scholar

Liu H, Fergusson MM, Castilho RM et al (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806Article

CAS

PubMed

Google Scholar

Doi S, Zou Y, Togao O et al (2011) Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 286:8655–8665Article

CAS

PubMed

PubMed Central

Google Scholar

López I, Rodríguez-Ortiz ME, Almadén Y et al (2011) Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int 80:475–482Article

PubMed

CAS

Google Scholar

Quarles LD (2012) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318:1040–1048Article

CAS

PubMed

PubMed Central

Google Scholar

Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V et al (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008CAS

PubMed

PubMed Central

Google Scholar

Krajisnik T, Bjorklund P, Marsell R et al (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131Article

CAS

PubMed

Google Scholar

Paloian NJ, Leaf EM, Giachelli CM (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027–1036Article

CAS

PubMed

PubMed Central

Google Scholar

Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–5270Article

CAS

Google Scholar

Ferron M, Wei J, Yoshizawa T et al (2010) Insulin signaling in osteoblasts integrates bone remodelling and energy metabolism. Cell 142:296–308Article

CAS

PubMed

PubMed Central

Google Scholar

Fulzele K, Riddle RC, DiGirolamo DJ et al (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319Article

CAS

PubMed

PubMed Central

Google Scholar

Lee NK, Karsenty G (2008) Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metab 19:161–166Article

CAS

PubMed

Google Scholar

Reid IR, Ames R, Evans MC et al (1992) Determinants of total body and regional bone mineral density in normal postmenopausal women—a key role for fat mass. J Clin Endocrinol Metab 75:45–51CAS

PubMed

Google Scholar

Ribot C, Tremollieres F, Pouilles JM et al (1987) Obesity and postmenopausal bone loss: the influence of obesity on vertebral density and bone turnover in postmenopausal women. Bone 8:327–331Article

CAS

PubMed

Google Scholar

Kindblom JM, Ohlsson C, Ljunggren Ö et al (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791Article

CAS

PubMed

Google Scholar

Pittas AG, Harris SS, Eliades M et al (2009) Association between serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab 94:827–832Article

CAS

PubMed

Google Scholar

Oury F, Sumara G, Sumara O et al (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809Article

CAS

PubMed

PubMed Central

Google Scholar

Sommerfeldt D, Rubin C (2001) Biology of bone and how it orchestrates the form and function of the skeleton. Eur Spine J 10:S86–S95Article

PubMed

PubMed Central

Google Scholar

Augat P, Schorlemmer S (2006) The role of cortical bone and its microstructure in bone strength. Age Ageing 35(suppl_2):ii27–ii31Article

PubMed

Google Scholar

Rho J-Y, Kuhn-Spearing L, Zioupos P (1998) Mechanical properties and the hierarchical structure of bone. Med Eng Phys 20:92–102Article

CAS

PubMed

Google Scholar

Van De Graaff K (2001) Skeletal system: introduction and the axial skeleton. In: Lange M, Tibbetts K, Queck K (eds) Human Anatomy, 6th edn. McGraw-Hill College, Boston, pp 131–171

Google Scholar

Weiner S, Traub W, Wagner HD (1999) Lamellar bone: structure-function relations. J Struct Biol 126:241–255Article

CAS

PubMed

Google Scholar

Meyer U, Wiesmann HP (2006) Bone and cartilage. In: Schröder G (ed) Bone and cartilage engineering, 1st edn. Springer, Berlin, pp. 7–46

Google Scholar

Oftadeh R, Perez-Viloria M, Villa-Camacho JC et al (2015) Biomechanics and mechanobiology of trabecular bone: a review. J Biomech Eng 137:010802Article

Google Scholar

Currey JD (2003) The many adaptations of bone. J Biomech 36:1487–1495Article

CAS

PubMed

Google Scholar

Burr DB, Milgrom C, Fyhrie D et al (1996) In vivo measurement of human tibial strains during vigorous activity. Bone 18:405–410Article

CAS

PubMed

Google Scholar

Duncan RL, Turner CH (1995) Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int 57:344–358Article

CAS

PubMed

Google Scholar

Zioupos P, Currey JD, Hamer AJ (1999) The role of collagen in the declining mechanical properties of aging human cortical bone. J Biomed Mater Res A 45:108–116Article

CAS

Google Scholar

Turner CH (2006) Bone strength: current concepts. Ann N Y Acad Sci 1068:429–446Article

PubMed

Google Scholar

Young MF (2003) Bone matrix proteins: their function, regulation, and relationship to osteoporosis. Osteoporos Int 14:35–42Article

CAS

Google Scholar

Bodian DL, Chan T-F, Poon A et al (2009) Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Gen 18:463–471Article

CAS

PubMed

Google Scholar

Fukada E, Yasuda I (1964) Piezoelectric effects in collagen. Jpn J Appl Phys 3:117–121Article

CAS

Google Scholar

Noris-Suárez K, Lira-Olivares J, Ferreira AM et al (2007) In vitro deposition of hydroxyapatite on cortical bone collagen stimulated by deformation-induced piezoelectricity. Biomacromol 8:941–948Article

CAS

Google Scholar

Ferreira AM, González G, González-Paz RJ et al (2009) Bone collagen role in piezoelectric mediated remineralization. Acta Microsc 18:278–286CAS

Google Scholar

Nudelman F, Pieterse K, George A et al (2010) The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nat Mater 9:1004–1009Article

CAS

PubMed

PubMed Central

Google Scholar

Ashizawa N, Graf K, Do YS et al (1996) Osteopontin is produced by rat cardiac fibroblasts and mediates A (II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 98:2218–2227Article

CAS

PubMed

PubMed Central

Google Scholar

Perrien DS, Brown EC, Aronson J et al (2002) Immunohistochemical study of osteopontin expression during distraction osteogenesis in the rat. J Histochem Cytochem 50:567–574Article

CAS

PubMed

Google Scholar

Gross TS, King KA, Rabaia NA et al (2005) Upregulation of osteopontin by osteocytes deprived of mechanical loading or oxygen. J Bone Miner Res 20:250–256Article

CAS

PubMed

Google Scholar

Harter LV, Hruska KA, Duncan RL (1995) Human osteoblast-like cells respond to mechanical strain with increased bone matrix protein production independent of hormonal regulation. Endocrinology 136:528–535Article

CAS

PubMed

Google Scholar

Fisher LW, Torchia DA, Fohr B et al (2001) Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun 280:460–465Article

CAS

PubMed

Google Scholar

Jahnen-Dechent W, Schäfer C, Ketteler M et al (2008) Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J Mol Med 86:379–389Article

CAS

PubMed

Google Scholar

Thurner PJ, Chen CG, Ionova-Martin S et al (2010) Osteopontin deficiency increases bone fragility but preserves bone mass. Bone 46:1564–1573Article

CAS

PubMed

PubMed Central

Google Scholar

Bentmann A, Kawelke N, Moss D et al (2010) Circulating fibronectin affects bone matrix, whereas osteoblast fibronectin modulates osteoblast function. J Bone Miner Res 25:706–715CAS

PubMed

Google Scholar

Huang G, Zhang Y, Kim B et al (2009) Fibronectin binds and enhances the activity of bone morphogenetic protein 1. J Biol Chem 284:25879–25888Article

CAS

PubMed

PubMed Central

Google Scholar

Kang Y, Georgiou AI, MacFarlane RJ et al (2017) Fibronectin stimulates the osteogenic differentiation of murine embryonic stem cells. J Tissue Eng Regen Med 11:1929–1940Article

CAS

PubMed

Google Scholar

Linsley C, Wu B, Tawil B (2013) The effect of fibrinogen, collagen type I, and fibronectin on mesenchymal stem cell growth and differentiation into osteoblasts. Tissue Eng Part A 19:1416–1423Article

CAS

PubMed

Google Scholar

Matlahov I, Iline-Vul T, Abayev M et al (2015) Interfacial mineral–peptide properties of a mineral binding peptide from osteonectin and bone-like apatite. Chem Mater 27:5562–5569Article

CAS

Google Scholar

Rosset EM, Bradshaw AD (2016) SPARC/osteonectin in mineralized tissue. Matrix Biol 52:78–87Article

PubMed

CAS

Google Scholar

Delany AM, Hankenson KD (2009) Thrombospondin-2 and SPARC/osteonectin are critical regulators of bone remodelling. J Cell Commun Signal 3:227–238Article

PubMed

PubMed Central

Google Scholar

Delany AM, Amling M, Priemel M et al (2000) Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest 105:915–923Article

CAS

PubMed

PubMed Central

Google Scholar

Wang M, Chao CC, Chen PC et al (2019) Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis. Biochem Pharmacol 166:23–32Article

CAS

PubMed

Google Scholar

Wang P, Tang C, Wu J et al (2019) Pulsed electromagnetic fields regulate osteocyte apoptosis, RANKL/OPG expression, and its control of osteoclastogenesis depending on the presence of primary cilia. J Cell Physiol 234:10588–10601Article

CAS

PubMed

Google Scholar

Ganss B, Kim RH, Sodek J (1999) Bone sialoprotein. Crit Rev Oral Biol Med 10:79–98Article

CAS

PubMed

Google Scholar

Malaval L, Wade-Guéye NM, Boudiffa M et al (2008) Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med 205:1145–1153Article

CAS

PubMed

PubMed Central

Google Scholar

Holm E, Aubin JE, Hunter GK et al (2015) Loss of bone sialoprotein leads to impaired endochondral bone development and mineralization. Bone 71:145–154Article

CAS

PubMed

Google Scholar

Bouleftour W, Juignet L, Verdière L et al (2019) Deletion of OPN in BSP knockout mice does not correct bone hypomineralization but results in high bone turnover. Bone 120:411–422Article

CAS

PubMed

Google Scholar

Lamoureux F, Baud’huin M, Duplomb L et al (2007) Proteoglycans: key partners in bone cell biology. BioEssays 29:758–771Article

CAS

PubMed

Google Scholar

Novince CM, Michalski MN, Koh AJ et al (2012) Proteoglycan 4: a dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism. J Bone Miner Res 27:11–25Article

CAS

PubMed

Google Scholar

Nakamura H (2007) Morphology, function, and differentiation of bone cells. J Hard Tissue Biol 16:15–22Article

CAS

Google Scholar

Palumbo C (1986) A three-dimensional ultrastructural study of osteoid-osteocytes in the tibia of chick embryos. Cell Tissue Res 246:125–131Article

CAS

PubMed

Google Scholar

Bellows CG, Reimers SM, Heersche JNM (1999) Expression of mRNAs for type-I collagen, bone sialoprotein, osteocalcin, and osteopontin at different stages of osteoblastic differentiation and their regulation by 1,25 dihydroxyvitamin D3. Cell Tissue Res 297:249–259Article

CAS

PubMed

Google Scholar

Bellows CG, Heersche JNM (2001) The frequency of common progenitors for adipocytes and osteoblasts and of committed and restricted adipocyte and osteoblast progenitors in fetal rat calvaria cell populations. J Bone Miner Res 16:1983–1993Article

CAS

PubMed

Google Scholar

Schiller PC, D’Ippolito G, Balkan W et al (2001) Gap-junctional communication is required for the maturation process of osteoblastic cells in culture. Bone 28:362–369Article

CAS

PubMed

Google Scholar

Komori T (2019) Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2. Int J Mol Sci 20:1694–1705Article

CAS

PubMed Central

Google Scholar

Rutkovskiy A, Stensløkken KO, Vaage IJ (2016) Osteoblast differentiation at a glance. Med Sci Mon Basic Res 22:95–106Article

Google Scholar

van der Meijden K, Bakker AD, van Essen HW et al (2016) Mechanical loading and the synthesis of 1, 25 (OH) 2 D in primary human osteoblasts. J Steroid Biochem Mol Biol 156:32–39Article

PubMed

CAS

Google Scholar

van Bezooijen RL, Roelen BA, Visser A et al (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814Article

PubMed

PubMed Central

CAS

Google Scholar

Bonewald LF (2007) Osteocyte messages from a bony tomb. Cell Metab 5:410–411Article

CAS

PubMed

Google Scholar

Jiang JX, Siller-Jackson AJ, Burra S (2007) Roles of gap junctions and hemichannels in bone cell functions and in signal transmission of mechanical stress. Front Biosci 12:1450–1462Article

CAS

PubMed

PubMed Central

Google Scholar

Tate ML Knothe, Adamson JR, Tami AE, Bauer TW (2004) The osteocyte. Int J Biochem Cell Biol 36:1–8Article

CAS

Google Scholar

Tate ML Knothe (2003) Whither flows the fluid in bone? An osteocyte’s perspective. J Biomech 36:1409–1424Article

Google Scholar

Burger EH, Klein-Nulend J (1999) Mechanotransduction in bone—role of the lacuno-canalicular network. FASEB J 13:101–112Article

Google Scholar

Mullender M, El Haj AJ, Yang Y et al (2004) Mechanotransduction of bone cells in vitro: mechanobiology of bone tissue. Med Biol Eng Comput 42:14–21Article

CAS

PubMed

Google Scholar

Huang CP, Chen XM, Chen ZQ (2008) Osteocyte: the impresario in the electrical stimulation for bone fracture healing. Med Hypotheses 70:287–290Article

PubMed

Google Scholar

Vasquez-Sancho F, Abdollahi A, Damjanovic D et al (2018) Flexoelectricity in bones. Adv Mater 30:1705316Article

CAS

Google Scholar

van Oers RF, Wang H, Bacabac RG (2015) Osteocyte shape and mechanical loading. Curr Osteoporos Rep 13:61–66Article

PubMed

PubMed Central

Google Scholar

Yu K, Sellman DP, Bahraini A et al (2018) Mechanical loading disrupts osteocyte plasma membranes which initiates mechanosensation events in bone. J Orthop Res 36:653–662CAS

PubMed

Google Scholar

Kringelbach TM, Aslan D, Novak I et al (2015) Fine-tuned ATP signals are acute mediators in osteocyte mechanotransduction. Cell Signal 27:2401–2409Article

CAS

PubMed

Google Scholar

Morrell AE, Brown GN, Robinson ST et al (2018) Mechanically induced Ca 2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation. Bone Res 6:6Article

PubMed

PubMed Central

CAS

Google Scholar

Cherian PP, Cheng B, Gu S et al (2003) Effects of mechanical strain on the function of gap junctions in osteocytes are mediated through the prostaglandin EP2 receptor. J Biol Chem 278:43146–43156Article

CAS

PubMed

Google Scholar

Klein-Nulend J, Helfrich MH, Sterck JGH et al (1998) Nitric oxide response to shear stress by human bone cell cultures is endothelial nitric oxide synthase dependent. Biochem Biophys Res Commun 250:108–114Article

CAS

PubMed

Google Scholar

Rawlinson SCF, Pitsillides AA, Lanyon LE (1996) Involvement of different ion channels in osteoblasts’ and osteocytes’ early responses to mechanical strain. Bone 19:609–614Article

CAS

PubMed

Google Scholar

Jee WSS, Mori S, Li XJ, Chan S (1990) Prostaglandin E2 enhances cortical bone mass and activates intracortical bone remodelling in intact and ovariectomized female rats. Bone 11:253–266Article

CAS

PubMed

Google Scholar

Fan X, Roy E, Zhu L et al (2004) Nitric oxide regulates receptor activator of nuclear factor κB ligand and osteoprotegerin expression in bone marrow stromal cells. Endocrinology 145:751–759Article

CAS

PubMed

Google Scholar

Kasten TP, Collin-Osdoby P, Patel N et al (1994) Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. Proc Natl Acad Sci USA 91:3569–3573Article

CAS

Google Scholar

Hirose S, Li M, Kojima T et al (2007) A histological assessment on the distribution of the osteocytic lacunar canalicular system using silver staining. J Bone Miner Metab 25:374–382Article

PubMed

Google Scholar

Jilka RL, Noble B, Weinstein RS (2013) Osteocyte apoptosis. Bone 54:264–271Article

PubMed

Google Scholar

Lee KC, Jessop H, Suswillo R et al (2004) The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta. Endocrinology 182:193–201Article

CAS

Google Scholar

Plotkin LI, Mathov I, Aguirre JI et al (2005) Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs. Am J Physiol 289:633–643Article

CAS

Google Scholar

Tomkinson A, Reeve J, Shaw RW, Noble BS (1997) The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab 82:3128–3135CAS

PubMed

Google Scholar

Metz LN, Martin RB, Turner AS (2003) Histomorphometric analysis of the effects of osteocyte density on osteonal morphology and remodelling. Bone 33:753–759Article

PubMed

Google Scholar

Milovanovic P, Zimmermann EA, Hahn M et al (2013) Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. ACS Nano 7:7542–7551Article

CAS

PubMed

Google Scholar

Okada S, Yoshida S, Ashrafi S, Schraufnagel D (2002) The Canalicular Structure of Compact Bone in the Rat at Different Ages. Microsc Microanal 8:104–115Article

CAS

PubMed

Google Scholar

Rubin J, Greenfield EM (2005) Osteoclast: origin and differentiation. In: Farach-Carson MC, Bronner F, Rubin J (eds) Bone resorption. Springer, London, pp 1–23

Google Scholar

Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40:251–264Article

CAS

PubMed

Google Scholar

Nakagawa N, Kinosaki M, Yamaguchi K et al (1998) RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 253:395–400Article

CAS

PubMed

Google Scholar

Takayanagi H (2008) Regulation of osteoclastogenesis and osteoimmunology. Bone 42:S40Article

Google Scholar

Marchisio PC, Cirillo D, Naldini L et al (1984) Cell-substratum interaction of cultured avian osteoclasts is mediated by specific adhesion structures. J Cell Biol 99:1696–1705Article

CAS

PubMed

Google Scholar

Väänänen HK, Horton M (1995) The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J Cell Sci 108:2729–2732PubMed

Google Scholar

Baron R, Neff L, Louvard D, Courtoy PJ (1985) Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border. J Cell Biol 101:2210–2222Article

CAS

PubMed

Google Scholar

Blair HC, Teitelbaum SL, Ghiselli R, Gluck S (1989) Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245:855–857Article

CAS

PubMed

Google Scholar

Rousselle AV, Heymann D (2002) Osteoclastic acidification pathways during bone resorption. Bone 30:533–540Article

CAS

PubMed

Google Scholar

Littlewood-Evans A, Kokubo T, Ishibashi O et al (1997) Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry. Bone 20:81–86Article

CAS

PubMed

Google Scholar

Vääräniemi J, Halleen JM, Kaarlonen K et al (2004) Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res 19:1432–1440Article

PubMed

CAS

Google Scholar

Salo J, Lehenkari P, Mulari M et al (1997) Removal of osteoclast bone resorption products by transcytosis. Science 276:270–273Article

CAS

PubMed

Google Scholar

Yamaki M, Nakamura H, Takahashi N et al (2005) Transcytosis of calcium from bone by osteoclast-like cells evidenced by direct visualization of calcium in cells. Arch Biochem Biophys 440:10–17Article

CAS

PubMed

Google Scholar

Harada SI, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423:349–355Article

CAS

PubMed

Google Scholar

Karsenty G, Kronenberg HM, Settembre C (2009) Genetic control of bone formation. Annu Rev Cell Dev Biol 25:629–648Article

CAS

PubMed

Google Scholar

Siddiqui JA, Partridge NC (2016) Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda) 31:233–245Article

CAS

PubMed

PubMed Central

Google Scholar

Murayama A, Takeyama K, Kitanaka S et al (1998) The promoter of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1α,25(OH)2D3. Biochem Biophys Res Commun 249:11–16Article

CAS

PubMed

Google Scholar

Haussler MR, Whitfield GK, Haussler CA et al (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13:325–349Article

CAS

PubMed

Google Scholar

Saini RK, Kaneko I, Jurutka PW et al (2013) 1, 25-dihydroxyvitamin d3 regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. Calcif Tissue Int 92:339–353Article

CAS

PubMed

Google Scholar

Clarke B (2008) Normal bone anatomy and physiology. Clin J Am Soc Nephrol 3:S131–S139Article

CAS

PubMed

PubMed Central

Google Scholar

Hong AR, Lee JH, Kim JH et al (2019) Effect of endogenous parathyroid hormone on bone geometry and skeletal microarchitecture. Calcif Tissue Int 104:382–389Article

CAS

PubMed

Google Scholar

Boissy P, Saltel F, Bouniol C et al (2002) Transcriptional activity of nuclei in multinucleated osteoclasts and its modulation by calcitonin. Endocrinology 143:1913–1921Article

CAS

PubMed

Google Scholar

Hadjidakis DJ, Androulakis II (2006) Bone remodelling. Ann NY Acad Sci 1092:385–396Article

CAS

PubMed

Google Scholar

Isaksson OG, Jansson JO, Gause IA (1982) Growth hormone stimulates longitudinal bone growth directly. Science 216:1237–1239Article

CAS

PubMed

Google Scholar

Ohlsson C, Bengtsson BA, Isaksson OG et al (1998) Growth hormone and bone. Endocrine Rev 19:55–79CAS

Google Scholar

Ranke MB, Wit JM (2018) Growth hormone—past, present and future. Nat Rev Endocrinol 14:285–300Article

CAS

PubMed

Google Scholar

Wu S, Yang W, De Luca F (2015) Insulin-like growth factor-independent effects of growth hormone on growth plate chondrogenesis and longitudinal bone growth. Endocrinology 156:2541–2551Article

CAS

PubMed

Google Scholar

Kuzma M, Kuzmova Z, Zelinkova Z et al (2014) Impact of the growth hormone replacement on bone status in growth hormone deficient adults. Growth Horm IGF Res 24:22–28Article

CAS

PubMed

Google Scholar

Guevarra MS, Yeh JK, Castro Magana M, Aloia JF (2010) Synergistic effect of parathyroid hormone and growth hormone on trabecular and cortical bone formation in hypophysectomized rats. Hormone Res Paediatr 73:248–257Article

CAS

Google Scholar

Lupu F, Terwilliger JD, Lee K et al (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229:141–162Article

CAS

PubMed

Google Scholar

Zhang M, Xuan S, Bouxsein ML et al (2002) Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem 277:44005–44012Article

CAS

PubMed

Google Scholar

Zhang W, Shen X, Wan C et al (2012) Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. Cell Biochem Funct 30:297–302Article

CAS

PubMed

Google Scholar

Fowlkes JL, Bunn RC, Liu L et al (2008) Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology 149:1697–1704Article

CAS

PubMed

Google Scholar

Chen JH, Liu C, You L, Simmons CA (2010) Boning up on Wolff’s Law: mechanical regulation of the cells that make and maintain bone. J Biomech 43:108–118Article

PubMed

Google Scholar

Ding W, Li J, Singh J et al (2015) miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE −/− mice. Cardiovasc Res 106:131–142Article

CAS

PubMed

PubMed Central

Google Scholar

Turner RT, Riggs BL, Spelsberg TC (1994) Skeletal effects of estrogen. Endocr Rev 15:275–300CAS

PubMed

Google Scholar

Khosla S, Monroe DG (2018) Regulation of bone metabolism by sex steroids. Cold Spring Harb Perspect Med 8:a031211Article

PubMed

PubMed Central

CAS

Google Scholar

Prince RL (1994) Counterpoint: estrogen effects on calcitropic hormones and calcium homeostasis. Endocr Rev 15:301–309Article

CAS

PubMed

Google Scholar

Liel Y, Shany S, Smirnoff P, Schwartz B (1999) Estrogen increases 1, 25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa 1. Endocrinology 140:280–285Article

CAS

PubMed

Google Scholar

ten Bolscher M, Netelenbos JC, Barto R, van Buuren LM (1999) Estrogen regulation of intestinal calcium absorption in the intact and ovariectomized adult rat. J Bone Miner Res 14:1197–1202Article

PubMed

Google Scholar

Draper CR, Edel MJ, Dick IM et al (1997) Phytoegens reduce bone loss and bone resorption in oophorectomized rats. J Nut 127:1795–1799Article

CAS

Google Scholar

Robinson LJ, Yaroslavskiy BB, Griswold RD et al (2009) Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-α with BCAR1 and Traf6. Exp Cell Res 315:1287–1301Article

CAS

PubMed

PubMed Central

Google Scholar

Väänänen HK (2005) Mechanism of osteoclast mediated bone resorption-rationale for the design of new therapeutics. Adv Drug Deliv Rev 57:959–971Article

PubMed

CAS

Google Scholar

Emerton KB, Hu B, Woo AA et al (2010) Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 46:577–583Article

CAS

PubMed

Google Scholar

Kousteni S, Chen JR, Bellido T et al (2002) Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298:843–846Article

CAS

PubMed

Google Scholar

Faloni APDS, Sasso-Cerri E, Rocha FRG et al (2012) Structural and functional changes in the alveolar bone osteoclasts of estrogen-treated rats. J Anat 220:77–85Article

CAS

PubMed

Google Scholar

Faloni APS, Sasso-Cerri E, Katchburian E, Cerri PS (2007) Decrease in the number and apoptosis of alveolar bone osteoclasts in estrogen-treated rats. J Periodont Res 42:193–201Article

CAS

Google Scholar

Hughes DE, Dai A, Tiffee JC et al (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-β. Nature Med 2:1132–1136Article

CAS

PubMed

Google Scholar

Khosla S, Oursler MJ, Monroe DG (2012) Estrogen and the skeleton. Trends Endocrinol Metab 23:576–581Article

CAS

PubMed

PubMed Central

Google Scholar

Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514Article

CAS

PubMed

Google Scholar

Riggs BL, Khosla S, Melton LJ (1998) A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763–773Article

CAS

PubMed

Google Scholar

Almeida M, Laurent MR, Dubois V et al (2016) Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97:135–187Article

PubMed Central

Google Scholar

Compston JE (2001) Sex steroids and bone. Physiol Rev 81:419–447Article

CAS

PubMed

Google Scholar

Vanderschueren D, Vandenput L, Boonen S et al (2004) Androgens and bone. Endocr Rev 25:389–425Article

CAS

PubMed

Google Scholar

Taaffe DR, Galvão DA, Spry N et al (2019) Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition. BJU Int 123:261–269Article

CAS

PubMed

Google Scholar

Bassett JD, Williams GR (2016) Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev 37:135–187Article

CAS

PubMed

PubMed Central

Google Scholar

El Hadidy M, Ghonaim M, El Gawad S, El Atta MA (2011) Impact of severity, duration, and etiology of hyperthyroidism on bone turnover markers and bone mineral density in men. BMC Endocr Disord 11:15Article

PubMed Central

CAS

Google Scholar

Harvey RD, McHardy KC, Reid IW et al (1991) Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers. J Clin Endocrinol Metab 72:1189–1194Article

CAS

PubMed

Google Scholar

Waring AC, Harrison S, Fink HA et al (2013) A prospective study of thyroid function, bone loss, and fractures in older men: The MrOS study. J Bone Miner Res 28:472–479Article

CAS

PubMed

Google Scholar

Britto JM, Fenton AJ, Holloway WR et al (1994) Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 134:169–176Article

CAS

PubMed

Google Scholar

Abe E, Marians RC, Yu W et al (2003) TSH is a negative regulator of skeletal remodelling. Cell 115:151–162Article

CAS

PubMed

Google Scholar

Sun L, Vukicevic S, Baliram R et al (2008) Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss. Proc Natl Acad Sci USA 105:4289–4294Article

CAS

Google Scholar

Neumann S, Eliseeva E, Boutin A et al (2018) Discovery of a positive allosteric modulator of the thyrotropin receptor: potentiation of thyrotropin-mediated preosteoblast differentiation in vitro. J Pharmacol Exp Ther 364:38–45Article

CAS

PubMed

PubMed Central

Google Scholar

Chen XX, Yang T (2015) Roles of leptin in bone metabolism and bone diseases. J Bone Miner Metab 33:474–485Article

CAS

PubMed

Google Scholar

Shi Y, Yadav VK, Suda N et al (2008) Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci USA 105:20529–20533Article

CAS

Google Scholar

Holloway WR, Collier FM, Aitken CJ et al (2002) Leptin inhibits osteoclast generation. J Bone Miner Res 17:200–209Article

CAS

PubMed

Google Scholar

Elefteriou F, Takeda S, Ebihara K et al (2004) Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA 101:3258–3263Article

CAS

Google Scholar

Hamrick MW, Ferrari SL (2008) Leptin and the sympathetic connection of fat to bone. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 19:905–912Article

CAS

Google Scholar

Turner RT, Kalra SP, Wong CP et al (2013) Peripheral leptin regulates bone formation. J Bone Miner Res 28:22–34Article

CAS

PubMed

Google Scholar

Mantzoros CS, Magkos F, Brinkoetter M et al (2011) Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 301:E567–E584Article

CAS

PubMed

PubMed Central

Google Scholar

DeBlasio MJ, Lanham SA, Blache D et al (2018) Sex-and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus. Am J Physiol Regul Integr Comp Physiol 314:R781–R790Article

CAS

Google Scholar

Maor G, Rochwerger M, Segev Y, Phillip M (2002) Leptin acts as a growth factor on the chondrocytes of skeletal growth centres. J Bone Miner Res 17:1034–1043Article

CAS

PubMed

Google Scholar

Ruys CA, van de Lagemaat M, Lafeber HN et al (2018) Leptin and IGF-1 in relation to body composition and bone mineralization of preterm-born children from infancy to 8 years. Clin Endocrinol 89:76–84Article

CAS

Google Scholar

Tsuji K, Maeda T, Kawane T et al (2010) Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1α25-dihydroxyvitamin D3 synthesis in leptin-deficient ob/ob mice. J Bone Miner Res 25:1711–1723Article

CAS

PubMed

Google Scholar

López I, Pineda C, Raya AI et al (2016) Leptin directly stimulates parathyroid hormone secretion. Endocrine Abstracts 41:GP144

Google Scholar

Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899Article

CAS

PubMed

Google Scholar

Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM (2005) BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA 102:18023–18027Article

CAS

Google Scholar

Beederman M, Lamplot JD, Nan G et al (2013) BMP signaling in mesenchymal stem cell differentiation and bone formation. J Biomed Sci Eng 6:32–52Article

PubMed

PubMed Central

CAS

Google Scholar

Rahman MS, Akhtar N, Jamil HM et al (2015) TGF-/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res 3:15005Article

CAS

PubMed

PubMed Central

Google Scholar

Lin GL, Hankenson KD (2011) Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem 112:3491–3501Article

CAS

PubMed

PubMed Central

Google Scholar

Kang Q, Song WX, Luo Q et al (2008) A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells Dev 18:545–559Article

PubMed Central

CAS

Google Scholar

Kang Q, Sun MH, Cheng H et al (2004) Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther 11:1312–1320Article

CAS

PubMed

Google Scholar

Huang E, Zhu G, Jiang W et al (2012) Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells. J Bone Miner Res 27:1566–1575Article

CAS

PubMed

Google Scholar

Li RD, Deng ZL, Hu N et al (2012) Biphasic effects of TGFβ1 on BMP9-induced osteogenic differentiation of mesenchymal stem cells. BMB Rep 45:509–514Article

CAS

PubMed

Google Scholar

Cheng H, Jiang W, Phillips FM et al (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 85:1544–1552Article

PubMed

Google Scholar

Franceschi RT, Wang D, Krebsbach PH, Rutherford RB (2000) Gene therapy for bone formation: in vitro and in vivo osteogenic activity of adenovirus expressing BMP-7. Ann Arbor 1001:48109–1078

Google Scholar

Jane JA Jr, Dunford BA, Kron A et al (2002) Ectopic osteogenesis using adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene transfer. Mol Ther 6:464–470Article

CAS

PubMed

Google Scholar

Carreira AC, Lojudice FH, Halcsik E et al (2014) Bone morphogenetic proteins facts, challenges, and future perspectives. J Dent Res 93:335–345Article

CAS

PubMed

Google Scholar

Cheng A, Krishnan L, Tran L et al (2019) The effects of age and dose on gene expression and segmental bone defect repair after BMP‐2 Delivery. JBMR Plus 3:e100681-11Article

PubMed

PubMed Central

CAS

Google Scholar

Holien T, Westhrin M, Moen SH et al (2018) BMP4 gene therapy inhibits myeloma tumor growth, but has a negative impact on bone. Blood 132:1928Article

Google Scholar

Frost HM (1987) Bone “mass” and the “mechanostat”: a proposal. Anat Rec 219:1–9Article

CAS

PubMed

Google Scholar

Corral DA, Amling M, Priemel M et al (1998) Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci USA 95:13835–13840Article

CAS

Google Scholar

Kong Y-Y, Feige U, Sarosi I et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309Article

CAS

PubMed

Google Scholar

Suda T, Takahashi N, Udagawa N et al (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20:345–357Article

CAS

PubMed

Google Scholar

Miyamoto T, Suda T (2003) Differentiation and function of osteoclasts. Keio J Med 52:1–7Article

PubMed

Google Scholar

Fan X, Rahnert JA, Murphy TC et al (2006) Response to mechanical strain in an immortalized pre-osteoblast cell is dependent on ERK1/2. J Cell Physiol 207:454–460Article

CAS

PubMed

Google Scholar

Kreja L, Liedert A, Hasni S, Claes L, Ignatius A (2008) Intermittent mechanical strain increases RANKL expression in human osteoblasts. J Biomech 41:S462Article

Google Scholar

Kim DW, Lee HJ, Karmin JA et al (2006) Mechanical loading differentially regulates membrane-bound and soluble RANKL availability in MC3T3-E1 cells. Ann NY Acad Sci 1068:568–572Article

CAS

PubMed

Google Scholar

Liu W, Xu C, Zhao H et al (2015) Osteoprotegerin induces apoptosis of osteoclasts and osteoclast precursor cells via the fas/fas ligand pathway. PLoS ONE 10:e0142519Article

PubMed

PubMed Central

CAS

Google Scholar

Arai F, Miyamoto T, Ohneda O et al (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κb (RANK) receptors. J Exp Med 190:1741–1754Article

CAS

PubMed

PubMed Central

Google Scholar

Romas E, Sims NA, Hards DK et al (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 161:1419–1427Article

CAS

PubMed

PubMed Central

Google Scholar

Kadow-Romacker A, Hoffmann JE, Duda G et al (2009) Effect of mechanical stimulation on osteoblast- and osteoclast-like cells in vitro. Cells Tissues Organs 190:61–68Article

CAS

PubMed

Google Scholar

Bentolila V, Boyce TM, Fyhrie DP et al (1998) Intracortical remodelling in adult rat long bones after fatigue loading. Bone 23:275–281Article

CAS

PubMed

Google Scholar

Mann V, Huber C, Kogianni G et al (2006) The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone. J Musculoskelet Neuronal Interact 6:408–417CAS

PubMed

Google Scholar

Martin RB (2007) Targeted bone remodelling involves BMU steering as well as activation. Bone 40:1574–1580Article

CAS

PubMed

Google Scholar

Mori S, Burr DB (1993) Increased intracortical remodelling following fatigue damage. Bone 14:103–109Article

CAS

PubMed

Google Scholar

Noble BS, Peet N, Stevens HY et al (2003) Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Physiol 284:934–943Article

Google Scholar

Verborgt O, Tatton NA, Majeska RJ, Schaffler MB (2002) Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodelling regulation? J Bone Miner Res 17:907–914Article

CAS

PubMed

Google Scholar

Tan SD, de Vries TJ, Kuijpers-Jagtman AM et al (2007) Osteocytes subjected to fluid flow inhibit osteoclast formation and bone resorption. Bone 41:745–751Article

CAS

PubMed

Google Scholar

Tan SD, Bakker AD, Semeins CM et al (2008) Inhibition of osteocyte apoptosis by fluid flow is mediated by nitric oxide. Biochem Biophys Res Commun 369:1150–1154Article

CAS

PubMed

Google Scholar

Rössig L, Haendeler J, Hermann C et al (2000) Nitric oxide down-regulates MKP-3 mRNA levels. J Biol Chem 275:25502–25507Article

PubMed

Google Scholar

Smalt R, Mitchell FT, Howard RL, Chambers TJ (1997) Induction of NO and prostaglandin E2 in osteoblasts by wall-shear stress but not mechanical strain. Am J Physiol 273:751–758

Google Scholar

Zaman G, Pitsillides AA, Rawlinson SCF et al (1999) Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res 14:1123–1131Article

CAS

PubMed

Google Scholar

van’T Hof RJ, Ralston SH (2001) Nitric oxide and bone. Immunology 103:255–261Article

Google Scholar

Canalis E, Adams DJ, Boskey A et al (2013) Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodelling. J Biol Chem 288:25614–25625Article

CAS

PubMed

PubMed Central

Google Scholar

Bullock WA, Pavalko FM, Robling AG (2019) Osteocytes and mechanical loading: the Wnt connection. Orthod Craniofac Res 22:175–179Article

PubMed

Google Scholar

Ferraro JT, Daneshmand M, Bizios R, Rizzo V (2004) Depletion of plasma membrane cholesterol dampens hydrostatic pressure and shear stress-induced mechanotransduction pathways in osteoblast cultures. Am J Physiol Cell Physiol 286:831–839Article

Google Scholar

Xing Y, Gu Y, Xu LC et al (2011) Effects of membrane cholesterol depletion and GPI-anchored protein reduction on osteoblastic mechanotransduction. J Cell Physiol 226:2350–2359Article

CAS

PubMed

PubMed Central

Google Scholar

Klausen TK, Hougaard C, Hoffmann EK, Pedersen SF (2006) Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin. Am J Physiol Cell Physiol 291:757–771Article

CAS

Google Scholar

Qi M, Liu Y, Freeman MR, Solomon KR (2009) Cholesterol-regulated stress fibre formation. J Cell Biochem 106:1031–1040Article

CAS

PubMed

Google Scholar

Dason JS, Smith AJ, Marin L, Charlton MP (2014) Cholesterol and F-actin are required for clustering of recycling synaptic vesicle proteins in the presynaptic plasma membrane. J Physiol 592:621–633Article

CAS

PubMed

PubMed Central

Google Scholar

Radel C, Rizzo V (2005) Integrin mechanotransduction stimulates caveolin-1 phosphorylation and recruitment of Csk to mediate actin reorganization. Am J Physiol 288:936–945

Google Scholar

Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339:269–280Article

CAS

PubMed

Google Scholar

Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687Article

CAS

PubMed

Google Scholar

Nievers MG, Schaapveld RQJ, Sonnenberg A (1999) Biology and function of hemidesmosomes. Matrix Biol 18:5–17Article

CAS

PubMed

Google Scholar

Matthews BD, Overby DR, Mannix R, Ingber DE (2006) Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. Journal Cell Sci 119:508–518Article

CAS

Google Scholar

Bhattacharya R, Gonzalez AM, DeBiase PJ et al (2009) Recruitment of vimentin to the cell surface by β3 integrin and plectin mediates adhesion strength. J Cell Sci 122:1390–1400Article

CAS

PubMed

PubMed Central

Google Scholar

Cram EJ, Schwarzbauer JE (2004) The talin wags the dog: new insights into integrin activation. Trends Cell Biol 14:55–57Article

CAS

PubMed

Google Scholar

Brown MC, Perrotta JA, Turner CE (1996) Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding. J Cell Biol 135:1109–1123Article

CAS

PubMed

Google Scholar

Geiger B, Spatz JP, Bershadsky AD (2009) Environmental sensing through focal adhesions. Nature Rev Mol Cell Biol 10:21–33Article

CAS

Google Scholar

El-Hoss J, Arabian A, Dedhar S, St-Arnaud R (2014) Inactivation of the integrin-linked kinase (ILK) in osteoblasts increases mineralization. Gene 533:246–252Article

CAS

PubMed

Google Scholar

Katz B-Z, Zamir E, Bershadsky A et al (2000) Physical state of the extracellular matrix regulates the structure and molecular composition of cell-matrix adhesions. Mol Biol Cell 11:1047–1060Article

CAS

PubMed

PubMed Central

Google Scholar

Parsons JT (1996) Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr Opin Cell Biol 8:146–152Article

CAS

PubMed

Google Scholar

Teo BKK, Wong ST, Lim CK et al (2013) Nanotopography modulates mechanotransduction of stem cells and induces differentiation through focal adhesion kinase. ACS Nano 7:4785–4798Article

CAS

PubMed

Google Scholar

Yamada KM, Geiger B (1997) Molecular interactions in cell adhesion complexes. Curr Opin Cell Biol 9:76–85Article

CAS

PubMed

Google Scholar

Hendesi H, Barbe MF, Safadi FF et al (2015) Integrin mediated adhesion of osteoblasts to connective tissue growth factor (CTGF/CCN2) induces cytoskeleton reorganization and cell differentiation. PLoS ONE 10(2):e0115325Article

PubMed

PubMed Central

CAS

Google Scholar

Moussa FM, Hisijara IA, Sondag GR et al (2014) Osteoactivin promotes osteoblast adhesion through HSPG and αvβ1 integrin. J Cell Biochem 115:1243–1253Article

CAS

PubMed

Google Scholar

Saidak Z, Le Henaff C, Azzi S et al (2015) Wnt/β-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5β1 integrin priming in mesenchymal skeletal cells. J Biol Chem 290:6903–6912Article

CAS

PubMed

PubMed Central

Google Scholar

Carvalho RS, Schaffer JL, Gerstenfeld LC (1998) Osteoblasts induce osteopontin expression in response to attachment on fibronectin: demonstration of a common role for integrin receptors in the signal transduction processes of cell attachment and mechanical stimulation. J Cell Biochem 70:376–390Article

CAS

PubMed

Google Scholar

Riveline D, Zamir E, Balaban NQ et al (2001) Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J Cell Biol 153:1175–1185Article

CAS

PubMed

PubMed Central

Google Scholar

Carvalho RS, Bumann A, Schaffer JL, Gerstenfeld LC (2002) Predominant integrin ligands expressed by osteoblasts show preferential regulation in response to both cell adhesion and mechanical perturbation. J Cell Biochem 84:497–508Article

CAS

PubMed

Google Scholar

Friedland JC, Lee MH, Boettiger D (2009) Mechanically activated integrin switch controls α5β1 function. Science 323:642–644Article

CAS

PubMed

Google Scholar

Litzenberger JB, Kim JB, Tummala P, Jacobs CR (2010) β1 integrins mediate mechanosensitive signaling pathways in osteocytes. Calcif Tissue Int 86:325–332Article

CAS

PubMed

PubMed Central

Google Scholar

Litzenberger JB, Tang WJ, Castillo AB, Jacobs CR (2009) Deletion of β1 integrins from cortical osteocytes reduces load-induced bone formation. Cell Mol Bioeng 2:416–424Article

CAS

Google Scholar

McNamara LM, Majeska RJ, Weinbaum S et al (2009) Attachment of osteocyte cell processes to the bone matrix. Anat Rec 292:355–363Article

CAS

Google Scholar

Phillips JA, Almeida EA, Hill EL et al (2008) Role for β1 integrins in cortical osteocytes during acute musculoskeletal disuse. Matrix Biol 27:609–618Article

CAS

PubMed

Google Scholar

Thi MM, Suadicani SO, Schaffler MB et al (2013) Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ3 integrin. Proc Natl Acad Sci USA 110:21012–21017Article

CAS

Google Scholar

Haugh MG, Vaughan TJ, McNamara LM (2015) The role of integrin α V β 3 in osteocyte mechanotransduction. J Mech Behav Biomed Mater 42:67–75Article

CAS

PubMed

Google Scholar

Cabahug-Zuckerman P, Stout RF Jr et al (2018) Potential role for a specialized β3 integrin-based structure on osteocyte processes in bone mechanosensation. J Orthop Res 36:642–652CAS

PubMed

Google Scholar

Pommerenke H, Schmidt C, Durr F et al (2002) The mode of mechanical integrin stressing controls intracellular signaling in osteoblasts. J Bone Miner Res 17:603–611Article

CAS

PubMed

Google Scholar

Saunders MM, You J, Trosko JE et al (2001) Gap junctions and fluid flow response in MC3T3-E1 cells. Am J Physiol—Cell Physiol 281:1917–1925Article

Google Scholar

Gillespie PG, Walker RG (2001) Molecular basis of mechanosensory transduction. Nature 413:194–202Article

CAS

PubMed

Google Scholar

Kazmierczak P, Sakaguchi H, Tokita J et al (2007) Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449:87–91Article

CAS

PubMed

Google Scholar

Marie PJ, Hay E (2013) Cadherins and Wnt signalling: a functional link controlling bone formation. BoneKEy Rep 2:4Article

CAS

Google Scholar

Matsuo K, Otaki N (2012) Bone cell interactions through Eph/ephrin: bone modeling, remodelling and associated diseases. Cell Adh Migr 6:148–156Article

PubMed

PubMed Central

Google Scholar

Tamma R, Zallone A (2012) Osteoblast and osteoclast crosstalks: from OAF to Ephrin. Inflamm Allergy-Drug Targets 11:196–200Article

CAS

PubMed

Google Scholar

Nakajima K, Kho DH, Yanagawa T et al (2016) Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management. Cancer Metastasis Rev 35:333–346Article

CAS

PubMed

PubMed Central

Google Scholar

Vinik Y, Shatz-Azoulay H, Vivanti A et al (2015) The mammalian lectin galectin-8 induces RANKL expression, osteoclastogenesis, and bone mass reduction in mice. Elife 4:e05914Article

PubMed

PubMed Central

Google Scholar

Tanikawa R, Tanikawa T, Hirashima M et al (2010) Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway. Biochem Biophys Res Commun 394:317–322Article

CAS

PubMed

Google Scholar

Flagg-Newton J, Simpson I, Loewenstein WR (1979) Permeability of the cell-to-cell membrane channels in mammalian cell junctions. Science 205:404–407Article

CAS

PubMed

Google Scholar

Steinberg TH, Civitelli R, Geist ST et al (1994) Connexin43 and connexin45 form gap junctions with different molecular permeabilities in osteoblastic cells. EMBO J 13:744–750Article

CAS

PubMed

PubMed Central

Google Scholar

Saunders MM, You J, Zhou Z et al (2003) Fluid flow-induced prostaglandin E2 response of osteoblastic ROS 17/2.8 cells is gap junction-mediated and independent of cytosolic calcium. Bone 32:350–356Article

CAS

PubMed

Google Scholar

Bivi N, Condon KW, Allen MR (2012) Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 27:374–389Article

CAS

PubMed

Google Scholar

Delaine-Smith RM, Sittichokechaiwut A, Reilly GC (2014) Primary cilia respond to fluid shear stress and mediate flow-induced calcium deposition in osteoblasts. FASEB J 28:430–439Article

CAS

PubMed

PubMed Central

Google Scholar

Myers KA, Rattner JB, Shrive NG, Hart DA (2007) Osteoblast-like cells and fluid flow: cytoskeleton-dependent shear sensitivity. Biochem Biophys Res Commun 364:214–219Article

CAS

PubMed

Google Scholar

Malone AMD, Anderson CT, Tummala P et al (2007) Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism. Proc Natl Acad Sci USA. 104:13325–13330Article

CAS

Google Scholar

Xiao Z, Zhang S, Mahlios J et al (2006) Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J Biol Chem 281:30884–30895Article

CAS

PubMed

Google Scholar

Leucht P, Monica SD, Temiyasathit S et al (2013) Primary cilia act as mechanosensors during bone healing around an implant. Med Eng Phys 35:392–402Article

CAS

PubMed

Google Scholar

Chen JC, Hoey DA, Chua M et al (2016) Mechanical signals promote osteogenic fate through a primary cilia-mediated mechanism. FASEB J 30:1504–1511Article

CAS

PubMed

Google Scholar

Coughlin TR, Voisin M, Schaffler MB et al (2015) Primary cilia exist in a small fraction of cells in trabecular bone and marrow. Calcif Tissue Int 96:65–72Article

CAS

PubMed

Google Scholar

Smith MA, Hoffman LM, Beckerle MC (2014) LIM proteins in actin cytoskeleton mechanoresponse. Trends Cell Biol 24:575–583Article

CAS

PubMed

PubMed Central

Google Scholar

Wang N, Ingber DE (1994) Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys J 66:2181–2189Article

CAS

PubMed

PubMed Central

Google Scholar

Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260:1124–1127Article

CAS

PubMed

Google Scholar

del Álamo JC, Norwich GN, Yshuan JL et al (2008) Anisotropic rheology and directional mechanotransduction in vascular endothelial cells. Proc Natl Acad Sci USA 105:15411–15416

Google Scholar

Hu S, Chen J, Fabry B et al (2003) Intracellular stress tomography reveals stress focusing and structural anisotropy in cytoskeleton of living cells. Am J Physiol 285:1082–1090Article

Google Scholar

Silberberg YR, Pelling AE, Yakubov GE et al (2008) Mitochondrial displacements in response to nanomechanical forces. J Mol Recognit 21:30–36Article

CAS

PubMed

Google Scholar

Koike M, Nojiri H, Ozawa Y et al (2015) Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Sci Rep 5:11722Article

CAS

PubMed

PubMed Central

Google Scholar

Khatiwala CB, Peyton SR, Putnam AJ (2006) Intrinsic mechanical properties of the extracellular matrix affect the behavior of pre-osteoblastic MC3T3-E1 cells. Am J Physiol Cell Physiol 290:1640–1650Article

CAS

Google Scholar

Wen JH, Vincent LG, Fuhrmann A et al (2014) Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat Mater 13:979–987Article

CAS

PubMed

PubMed Central

Google Scholar

Ritz U, Götz H, Baranowski A et al (2016) Influence of different calcium phosphate ceramics on growth and differentiation of cells in osteoblast–endothelial co-cultures. J Biomed Mater Res B Appl Biomater 105:1950–1962Article

PubMed

CAS

Google Scholar

Olivares-Navarrete R, Rodil SE, Hyzy SL et al (2015) Role of integrin subunits in mesenchymal stem cell differentiation and osteoblast maturation on graphitic carbon-coated microstructured surfaces. Biomaterials 51:69–79Article

CAS

PubMed

PubMed Central

Google Scholar

Fraioli R, Rechenmacher F, Neubauer S et al (2015) Mimicking bone extracellular matrix: Integrin-binding peptidomimetics enhance osteoblast-like cells adhesion, proliferation, and differentiation on titanium. Colloids Surf B 128:191–200Article

CAS

Google Scholar

Vatsa A, Breuls RG, Semeins CM et al (2008) Osteocyte morphology in fibula and calvaria—is there a role for mechanosensing? Bone 43:452–458Article

PubMed

Google Scholar

Van Hove RP, Nolte PA, Vatsa A et al (2009) Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density—is there a role for mechanosensing? Bone 45:321–329Article

PubMed

Google Scholar

Murshid SA, Kamioka H, Ishihara Y et al (2007) Actin and microtubule cytoskeletons of the processes of 3D-cultured MC3T3-E1 cells and osteocytes. J Bone Miner Metab 25:259Article

CAS

Google Scholar

Adachi T, Aonuma Y, Tanaka M et al (2009) Calcium response in single osteocytes to locally applied mechanical stimulus: Differences in cell process and cell body. J Biomech 42:1989–1995Article

PubMed

Google Scholar

Sugawara Y, Ando R, Kamioka H et al (2008) The alteration of a mechanical property of bone cells during the process of changing from osteoblasts to osteocytes. Bone 43:19–24Article

PubMed

Google Scholar

Prendergast PJ, Huiskes R (1995) The biomechanics of Wolff’s law: recent advances. Ir J Med Sci 164:152–154Article

CAS

PubMed

Google Scholar

Turner CH (1998) Three rules for bone adaptation to mechanical stimuli. Bone 23:399–407Article

CAS

PubMed

Google Scholar

Hsieh Y-F, Turner CH (2001) Effects of loading frequency on mechanically induced bone formation. J Bone Miner Res 16:918–924Article

CAS

PubMed

Google Scholar

Zhu J, Zhang X, Wang C et al (2008) Different magnitudes of tensile strain induce human osteoblasts differentiation associated with the activation of ERK1/2 phosphorylation. Int J Mol Sci 9:2322–2332Article

CAS

PubMed

PubMed Central

Google Scholar

Mosley JR, March BM, Lynch J, Lanyon LE (1997) Strain magnitude related changes in whole bone architecture in growing rats. Bone 20:191–198Article

CAS

PubMed

Google Scholar

Cullen DM, Smith RT, Akhter MP (2001) Bone-loading response varies with strain magnitude and cycle number. J Appl Physiol 91:1971–1976Article

CAS

PubMed

Google Scholar

Rubin CT, Lanyon LE (1984) Regulation of bone formation by applied dynamic loads. J Bone Joint Surg 66:397–402Article

CAS

PubMed

Google Scholar

Srinivasan S, Ausk BJ, Poliachik SL et al (2007) Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles. J Appl Physiol 102:1945–1952Article

PubMed

Google Scholar

Pereira AF, Shefelbine SJ (2014) The influence of load repetition in bone mechanotransduction using poroelastic finite-element models: the impact of permeability. Biomechan Model Mechanobiol 13:215–225Article

Google Scholar

Stavenschi E, Corrigan MA, Johnson GP et al (2018) Physiological cyclic hydrostatic pressure induces osteogenic lineage commitment of human bone marrow stem cells: a systematic study. Stem Cell Res Ther 9:276Article

PubMed

PubMed Central

CAS

Google Scholar

Warden SJ, Turner CH (2004) Mechanotransduction in the cortical bone is most efficient at loading frequencies of 5–10 Hz. Bone 34:261–270Article

CAS

PubMed

Google Scholar

Verbruggen SW, Vaughan TJ, McNamara LM (2014) Fluid flow in the osteocyte mechanical environment: a fluid–structure interaction approach. Biomechan model mechanobiol 13:85–97Article

Google Scholar

Wittig NK, Laugesen M, Birkbak ME et al (2019) Canalicular junctions in the osteocyte lacuno-canalicular network of cortical bone. ACS Nano 13:6421–6430Article

CAS

PubMed

Google Scholar

Gatti V, Azoulay EM, Fritton SP (2018) Microstructural changes associated with osteoporosis negatively affect loading-induced fluid flow around osteocytes in cortical bone. J Biomech 66:127–136Article

PubMed

Google Scholar

Nauli SM, Alenghat FJ, Luo Y et al (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet 33:129–137Article

CAS

PubMed

Google Scholar

Praetorius HA, Frokiaer J, Nielsen S, Spring KR (2003) Bending the primary cilium opens Ca2+-sensitive intermediate-conductance K+ channels in MDCK Cells. J Membr Biol 191:193–200Article

CAS

PubMed

Google Scholar

Waychunas GA (2014) Disrupting dissolving ions at surfaces with fluid flow. Science 344:1094–1095Article

CAS

PubMed

Google Scholar

Gross D, Williams WS (1982) Streaming potential and the electromechanical response of physiologically-moist bone. J Biomech 15:277–295Article

CAS

PubMed

Google Scholar

Frijns A, Huyghe J, Wijlaars M (2005) Measurements of deformations and electrical potentials in a charged porous medium. In: Gladwell GML, Huyghe J, Raats PA, Cowin SC (eds) IUTAM symposium on physicochemical and electromechanical interactions in porous media, vol 125, pp 133–139. Springer, Dordrecht

Google Scholar

Hong J, Ko S, Khang G, Mun M (2008) Intraosseous pressure and strain generated potential of cylindrical bone samples in the drained uniaxial condition for various loading rates. J Mater Sci Mater Med 19:2589–2594Article

CAS

PubMed

Google Scholar

Pienkowski D, Pollack SR (1983) The origin of stress-generated potentials in fluid-saturated bone. J Orthop Res 1:30–41Article

CAS

PubMed

Google Scholar

Iatridis J, Laible J, Krag M (2003) Influence of fixed charge density magnitude and distribution on the intervertebral disc: applications of a poroelastic and chemical electric (PEACE) model. J Biomech Eng 125:12–24Article

PubMed

Google Scholar

Fukada E, Yasuda I (1957) On the piezoelectric effect of bone. J Phys Soc Jpn 12:1158–1162Article

Google Scholar

Elmessiery MA (1981) Physical basis for piezoelectricity of bone matrix. IEE Proc A 128:336–346CAS

Google Scholar

Halperin C, Mutchnik S, Agronin A et al (2004) Piezoelectric effect in human bones studied in nanometer scale. Nano Lett 4:1253–1256Article

CAS

Google Scholar

Marino AA, Becker RO (1974) Piezoelectricity in bone as a function of age. Calcif Tissue Int 14:327–331Article

CAS

Google Scholar

Wang T, Feng Z, Song Y, Chen X (2007) Piezoelectric properties of human dentin and some influencing factors. Dent Mater 23:450–453Article

CAS

PubMed

Google Scholar

Reinish GB, Nowick AS (1975) Piezoelectric properties of bone as functions of moisture content. Nature 253:626–627Article

Google Scholar

Ahn AC, Grodzinsky AJ (2009) Relevance of collagen piezoelectricity to “Wolff’s Law”: a critical review. Med Eng Phys 31:733–741Article

PubMed

PubMed Central

Google Scholar

Ramtani S (2008) Electro-mechanics of bone remodelling. Int J Eng Sci 46:1173–1182Article

Google Scholar

Frias C, Reis J, e Silva FC et al (2010) Polymeric piezoelectric actuator substrate for osteoblast mechanical stimulation. J Biomech 43:1061–1066Article

CAS

PubMed

Google Scholar

Reis J, Frias C, Canto e Castro C, Botelho ML, Marques AT, Simões JA, Capela e Silva F, Potes J (2012) A new piezoelectric actuator induces bone formation in vivo: a preliminary study. BioMed Res Int 613403

Google Scholar

Zhang Y, Chen L, Zeng J et al (2014) Aligned porous barium titanate/hydroxyapatite composites with high piezoelectric coefficients for bone tissue engineering. Mater Sci Eng C 39:143–149Article

CAS

Google Scholar

Liu J, Gu H, Liu Q, Ren L, Li G (2019) An intelligent material for tissue reconstruction: The piezoelectric property of polycaprolactone/barium titanate composites. Mater Lett 236:686–689Article

CAS

Google Scholar

Jacob J, More N, Kalia K, Kapusetti G (2018) Piezoelectric smart biomaterials for bone and cartilage tissue engineering. Inflamm Regen 38:2Article

PubMed

PubMed Central

CAS

Google Scholar

Damaraju SM, Shen Y, Elele E, Khusid B, Eshghinejad A, Li J, Jaffe M, Arinzeh TL (2017) Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation. Biomaterials 149:51–62Article

CAS

PubMed

Google Scholar

Download references AcknowledgementsThis work has been partially supported by the European Commission under the 7th Framework Programme through the project Restoration, grant agreement CP-TP 280575-2 and through Portugal 2020/Alentejo 2020, grant POCI-01-0145-FEDER-032486. The support from Hamamatsu Photonics in providing the NanoZoomer SQ is also gratefully acknowledged. The authors would also like to thank Mr. Pedro Félix Pinto for the artwork included in this chapter that he so kindly prepared and made available. Author informationAuthors and AffiliationsEscola de Ciências e Tecnologia, Universidade de Évora, Largo dos Colegiais, Évora, PortugalJoana da Costa Reis & Maria Teresa OliveiraAuthorsJoana da Costa ReisView author publicationsYou can also search for this author in

PubMed Google ScholarMaria Teresa OliveiraView author publicationsYou can also search for this author in

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Joana da Costa Reis or Maria Teresa Oliveira . Editor informationEditors and AffiliationsDepartment of Mechanical Engineering, School of Engineering, Polytechnic of Porto (ISEP), Porto, PortugalJorge Belinha Departament de Patologia i Terapèutica Experimental, University of Barcelona, Barcelona, SpainMaria-Cristina Manzanares-Céspedes Department of Mechanical Engineering, University of Aveiro, Aveiro, PortugalAntónio M. G. Completo Rights and permissionsReprints and permissions Copyright information© 2020 Springer Nature Switzerland AG About this chapterCite this chapterda Costa Reis, J., Oliveira, M.T. (2020). Bone: Functions, Structure and Physiology.

In: Belinha, J., Manzanares-Céspedes, MC., Completo, A. (eds) The Computational Mechanics of Bone Tissue. Lecture Notes in Computational Vision and Biomechanics, vol 35. Springer, Cham. https://doi.org/10.1007/978-3-030-37541-6_1Download citation.RIS.ENW.BIBDOI: https://doi.org/10.1007/978-3-030-37541-6_1Published: 12 February 2020

Publisher Name: Springer, Cham

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imtoken钱包下载新版本|bone

imtoken钱包下载新版本|bone

BONE中文(简体)翻译：剑桥词典

Page restricted | ScienceDirect

Bone | Definition, Anatomy, & Composition | Britannica

Bone Research

Bones: Anatomy, function, types and clinical aspects | Kenhub

Mechanisms of bone development and repair | Nature Reviews Molecular Cell Biology

6.3 Bone Structure – Anatomy & Physiology

Bone - Structure, Function, Types | Britannica

Bone: Functions, Structure and Physiology | SpringerLink

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imtoken钱包下载新版本|bone

imtoken钱包下载新版本|bone

BONE中文(简体)翻译：剑桥词典

Page restricted | ScienceDirect

Bone | Definition, Anatomy, & Composition | Britannica

Bone Research

Bones: Anatomy, function, types and clinical aspects | Kenhub

Mechanisms of bone development and repair | Nature Reviews Molecular Cell Biology

6.3 Bone Structure – Anatomy & Physiology

Bone - Structure, Function, Types | Britannica

Bone: Functions, Structure and Physiology | SpringerLink

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