Current Osteoporosis Reports

, Volume 15, Issue 4, pp 318–325 | Cite as

Osteocyte Mechanobiology

  • Yuhei Uda
  • Ehab Azab
  • Ningyuan Sun
  • Chao Shi
  • Paola Divieti PajevicEmail author
Osteocytes (T Bellido and J Klein-Nulend, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Osteocytes


Purpose of Review

Over the past decades, osteocytes have emerged as mechano-sensors of bone and master regulators of bone homeostasis. This article summarizes latest research and progress made in understanding osteocyte mechanobiology and critically reviews tools currently available to study these cells.

Recent Findings

Whereas increased mechanical forces promote bone formation, decrease loading is always associated with bone loss and skeletal fragility. Recent studies identified cilia, integrins, calcium channels, and G-protein coupled receptors as important sensors of mechanical forces and Ca2+ and cAMP signaling as key effectors. Among transcripts regulated by mechanical forces, sclerostin and RANKL have emerged as potential therapeutic targets for disuse-induced bone loss.


In this paper, we review the mechanisms by which osteocytes perceive and transduce mechanical cues and the models available to study mechano-transduction. Future directions of the field are also discussed.


Osteocyte Mechanical forces Sclerostin Bone homeostasis 


Compliance with Ethical Standards

Conflict of Interest

Yuhei Uda, Chao Shi, Ehab Azab, and Ningyuan Sun declare no conflict of interest.

Divieti Pajevic reports grants from NIH/NIAMS during the conduct of the study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone. 2008;42(4):606–15.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    •• Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007;5(6):464–75. This study provide the fisrt scientific evidence that osteocytes are mechano-sensors. PubMedCrossRefGoogle Scholar
  3. 3.
    Bonewald L. Osteocytes as multifunctional cells. J Musculoskelet Neuronal Interact. 2006;6(4):331–3.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med.17(10):1231–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, and O’Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med.17(10):1235–41.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Wolff J. Das Gesetz der Transformation der Knochen Kirschwald. 1892.Google Scholar
  7. 7.
    Frost HM. Bone “mass” and the “mechanostat”: a proposal. Anat Rec. 1987;219:1–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Fulzele K, Lai F, Dedic C, Saini V, Uda Y, Shi C, et al. Osteocyte-secreted Wnt signaling inhibitor sclerostin contributes to beige adipogenesis in peripheral fat depots. J Bone Miner Res. 2017;32(2):373–84.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ingber DE. Tensegrity: the architectural basis of cellular mechanotransduction. Annu Rev Physiol. 1997;59:575–99.PubMedCrossRefGoogle Scholar
  10. 10.
    Vogel V, Sheetz M. Local force and geometry sensing regulate cell functions. Nat Rev Mol Cell Biol. 2006;7(4):265–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Burger EH, Klein-Nulend J. Mechanotransduction in bone—role of the lacuno-canalicular network. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 1999;13(Suppl):S101–12.CrossRefGoogle Scholar
  12. 12.
    Pal S. Mechanical properties of biological materials. 2014;23–40.Google Scholar
  13. 13.
    Ozcivici E, Luu YK, Adler B, Qin YX, Rubin J, Judex S, et al. Mechanical signals as anabolic agents in bone. Nat Rev Rheumatol. 2010;6(1):50–9.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Smith SM, Zwart SR, Heer M, Hudson EK, Shackelford L, Morgan JL. Men and women in space: bone loss and kidney stone risk after long-duration spaceflight. J Bone Miner Res. 2014;29(7):1639–45.PubMedCrossRefGoogle Scholar
  15. 15.
    Ohshima H. Bone loss and bone metabolism in astronauts during long-duration space flight. Clinical calcium. 2006;16(1):81–5.PubMedGoogle Scholar
  16. 16.
    Takano-Yamamoto T. Osteocyte function under compressive mechanical force. Japanese Dental Science Review. 2014;50(2):29–39.CrossRefGoogle Scholar
  17. 17.
    Cowin SC, Moss-Salentijn L, Moss ML. Candidates for the mechanosensory system in bone. J Biomech Eng. 1991;113(2):191–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech. 1994;27(3):339–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Kwon RY, Meays DR, Meilan AS, Jones J, Miramontes R, Kardos N, et al. Skeletal adaptation to intramedullary pressure-induced interstitial fluid flow is enhanced in mice subjected to targeted osteocyte ablation. PLoS One. 2012;7(3):e33336.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Riehl BD, Lee JS, Ha L, Kwon IK, Lim JY. Flowtaxis of osteoblast migration under fluid shear and the effect of RhoA kinase silencing. PLoS One. 2017;12(2):e0171857.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Liu CL, Li SN, Ji BH, Huo B. Flow-induced migration of osteoclasts and regulations of calcium signaling pathways. Cell Mol Bioeng. 2015;8(1):213–23.CrossRefGoogle Scholar
  22. 22.
    Miyauchi A, Gotoh M, Kamioka H, Notoya K, Sekiya H, Takagi Y, et al. AlphaVbeta3 integrin ligands enhance volume-sensitive calcium influx in mechanically stretched osteocytes. J Bone Miner Metab. 2006;24(6):498–504.PubMedCrossRefGoogle Scholar
  23. 23.
    Weyts FA, Li YS, van Leeuwen J, Weinans H, Chien S. ERK activation and alpha v beta 3 integrin signaling through Shc recruitment in response to mechanical stimulation in human osteoblasts. J Cell Biochem. 2002;87(1):85–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Yavropoulou MP, Yovos JG. The molecular basis of bone mechanotransduction. J Musculoskelet Neuronal Interact. 2016;16(3):221–36.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Weinbaum S, Duan Y, Thi MM, You L. An integrative review of mechanotransduction in endothelial, epithelial (renal) and dendritic cells (osteocytes). Cell Mol Bioeng. 2011;4(4):510–37.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hoey DA, Chen JC, Jacobs CR. The primary cilium as a novel extracellular sensor in bone. Front Endocrinol. 2012;3:75.CrossRefGoogle Scholar
  27. 27.
    Lee KL, Guevarra MD, Nguyen AM, Chua MC, Wang Y, Jacobs CR. The primary cilium functions as a mechanical and calcium signaling nexus. Cilia. 2015;4:7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Bell A. The pipe and the pinwheel: is pressure an effective stimulus for the 9+0 primary cilium? Cell Biol Int. 2008;32(4):462–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Qiu N, Xiao Z, Cao L, Buechel MM, David V, Roan E, et al. Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia. J Cell Sci. 2012;125(Pt 8):1945–57.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Xiao Z, Dallas M, Qiu N, Nicolella D, Cao L, Johnson M, et al. Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J. 25(7):2418–32.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Xiao Z, Zhang S, Mahlios J, Zhou G, Magenheimer BS, Guo D, et al. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J Biol Chem. 2006;281(41):30884–95.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Temiyasathit S, Tang WJ, Leucht P, Anderson CT, Monica SD, Castillo AB, et al. Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. PLoS One. 2012;7(3):e33368.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Xiao Z, Quarles LD. Physiological mechanisms and therapeutic potential of bone mechanosensing. Rev Endocr Metab Disord. 2015;16(2):115–29.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38.CrossRefGoogle Scholar
  35. 35.
    Wu XT, Sun LW, Yang X, Ding D, Han D, Fan YB. The potential role of spectrin network in the mechanotransduction of MLO-Y4 osteocytes. Scientific reports. 2017;7:40940.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Camirand A, Goltzman D, Gupta A, Kaouass M, Panda D, Karaplis A. The role of parathyroid hormone-related protein (PTHrP) in osteoblast response to microgravity: mechanistic implications for osteoporosis development. PLoS One. 2016;11(7):e0160034.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Delgado-Calle J, Tu X, Pacheco-Costa R, McAndrews K, Edwards R, Pellegrini GG, et al. Control of bone anabolism in response to mechanical loading and PTH by distinct mechanisms downstream of the PTH receptor. J Bone Miner Res. 2017;32(3):522–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Jacobs CR, Temiyasathit S, Castillo AB. Osteocyte mechanobiology and pericellular mechanics. Annu Rev Biomed Eng. 12:369–400.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Thi MM, Suadicani SO, Schaffler MB, Weinbaum S, Spray DC. Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require alphaVbeta3 integrin. Proc Natl Acad Sci U S A. 2013;110(52):21012–7. This study emonstrated the polarity of mechanosensing and mechanotransduction in osteocytes and its dependence on the αvβ3 integrin attachment. PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Na S, Collin O, Chowdhury F, Tay B, Ouyang M, Wang Y, et al. Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc Natl Acad Sci U S A. 2008;105(18):6626–31.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, et al. Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell. 2005;16(7):3100–6.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Cheng B, Kato Y, Zhao S, Luo J, Sprague E, Bonewald LF, et al. PGE(2) is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. Endocrinology. 2001;142(8):3464–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Cheng B, Zhao S, Luo J, Sprague E, Bonewald LF, Jiang JX. Expression of functional gap junctions and regulation by fluid flow in osteocyte-like MLO-Y4 cells. J Bone Miner Res. 2001;16(2):249–59.PubMedCrossRefGoogle Scholar
  44. 44.
    Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, et al. Mechanical strain opens Connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell. 2005;Google Scholar
  45. 45.
    Wang W, Ha CH, Jhun BS, Wong C, Jain MK, Jin ZG. Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS. Blood. 2010;115(14):2971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Wein MN, Liang Y, Goransson O, Sundberg TB, Wang J, Williams EA, O’Meara MJ, Govea N, Beqo B, and Nishimori S. SIKs control osteocyte responses to parathyroid hormone. Nature communications. 2016;7.Google Scholar
  47. 47.
    Lee K, Jessop H, Suswillo R, Zaman G, Lanyon L. Endocrinology: bone adaptation requires oestrogen receptor-alpha. Nature. 2003;424(6947):389.PubMedCrossRefGoogle Scholar
  48. 48.
    Ciani C, Sharma D, Doty SB, Fritton SP. Ovariectomy enhances mechanical load-induced solute transport around osteocytes in rat cancellous bone. Bone. 2014;59:229–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Sinnesael M, Laurent MR, Jardi F, Dubois V, Deboel L, Delisser P, et al. Androgens inhibit the osteogenic response to mechanical loading in adult male mice. Endocrinology. 2015;156(4):1343–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Lau KH, Baylink DJ, Zhou XD, Rodriguez D, Bonewald LF, Li Z, et al. Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. Am J Physiol Endocrinol Metab. 2013;305(2):E271–81.PubMedCrossRefGoogle Scholar
  51. 51.
    Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39(2):91–7.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem. 2003;278(26):24113–7.PubMedCrossRefGoogle Scholar
  53. 53.
    • Gaudio A, Pennisi P, Bratengeier C, Torrisi V, Lindner B, Mangiafico RA, et al. Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab. 95(5):2248–53. This study demosntrated an increase in serum sclerostin in immobilized patients. CrossRefGoogle Scholar
  54. 54.
    • Spatz JM, Fields EE, Yu EW, Divieti Pajevic P, Bouxsein ML, Sibonga JD, Zwart SR, and Smith SM. Serum sclerostin increases in healthy adult men during bed rest. J Clin Endocrinol Metab.97(9):E1736–40. This study demosntrated an increase in serum sclerostin in helathy volunteer under bed-rest. CrossRefGoogle Scholar
  55. 55.
    •• Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283(9):5866–75. Fisrt study demosntrating thst sclerostin is regulated by mechanical forces. PubMedCrossRefGoogle Scholar
  56. 56.
    Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading via antagonizing Wnt/beta-catenin signaling. J Bone Miner Res. 2009;24:1651–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, et al. Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res. 28(4):865–74.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Spatz JM, Wein MN, Gooi JH, Qu Y, Garr JL, Liu S, et al. The Wnt inhibitor sclerostin is up-regulated by mechanical unloading in osteocytes in vitro. J Biol Chem. 2015;290(27):16744–58.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kulkarni RN, Bakker AD, Everts V, Klein-Nulend J. Inhibition of osteoclastogenesis by mechanically loaded osteocytes: involvement of MEPE. Calcif Tissue Int. 2010;87(5):461–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–33.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bonewald LF. Establishment and characterization of an osteocyte-like cell line, MLO-Y4. J Bone Miner Metab. 1999;17(1):61–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Divieti P, Inomata N, Chapin K, Singh R, Juppner H, Bringhurst FR. Receptors for the carboxyl-terminal region of pth(1-84) are highly expressed in osteocytic cells. Endocrinology. 2001;142(2):916–25.PubMedCrossRefGoogle Scholar
  63. 63.
    Woo SM, Rosser J, Dusevich V, Kalajzic I, Bonewald LF. Cell line IDG-SW3 replicates osteoblast-to-late-osteocyte differentiation in vitro and accelerates bone formation in vivo. J Bone Miner Res. 2011;26(11):2634–46.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yuhei Uda
    • 1
  • Ehab Azab
    • 1
  • Ningyuan Sun
    • 1
  • Chao Shi
    • 1
    • 2
  • Paola Divieti Pajevic
    • 1
    • 3
    Email author
  1. 1.Molecular and Cell BiologyBoston University Henry M. Goldman School of Dental MedicineBostonUSA
  2. 2.Department of OrthopaedicsThe Second Affiliated Hospital of Xi’an Jiaotong UniversityShaanxi ProvincePeople’s Republic of China
  3. 3.BostonUSA

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