Skip to main content

Basic Aspects of Osteocyte Function

  • Chapter
  • First Online:
Osteoporosis

Part of the book series: Contemporary Endocrinology ((COE))

  • 1961 Accesses

Abstract

Exciting discoveries over the last years have propelled osteocytes, originally considered passive and metabolically inactive bone cells, to the category of master regulators of bone homeostasis. Osteocytes differentiate from osteoblasts when they become surrounded by matrix during the process of bone formation. Osteoblast to osteocyte differentiation is complex and involves profound modifications in gene expression that result in morphological changes and transform osteocytes in dynamic and multifunctional cells. In addition to the traditional role of osteocytes in the integration of mechanical signals, new osteocytic functions are emerging. Osteocytes are now considered a major source of molecules that coordinate the activity of osteoclasts and osteoblasts in response to both physical and hormonal cues. In addition, accumulating evidence supports the notion that dysregulation of osteocyte function underlies the pathophysiology of several skeletal disorders, ranging from rare to common diseases such as osteoporosis. Further, the increased understanding of osteocyte biology has led to the development of therapeutic approaches targeting osteocytes and their derived factors. In this chapter, we summarize the current knowledge on osteocyte biology and its different functions and discuss novel observations that support the role of osteocytes as endocrine regulators of body composition and energy metabolism and as key players in the deleterious effects of cancer and diabetes on bone.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Parfitt AM. Life history of osteocytes: relationship to bone age, bone remodeling. and bone fragility J Musculoskelet Neuronal Interact. 2002;2(6):499–500.

    CAS  PubMed  Google Scholar 

  2. Plotkin LI, Bellido T. Osteocytic signalling pathways as therapeutic targets for bone fragility. Nat Rev Endocrinol. 2016;12(10):593–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang K, Barragan-Adjemian C, Ye L, Kotha S, Dallas M, Lu Y, et al. E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol Cell Biol. 2006;26(12):4539–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Skupien A, Konopka A, Trzaskoma P, Labus J, Gorlewicz A, Swiech L, et al. CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi. J Cell Sci. 2014;127(Pt 23):5038–51.

    Article  PubMed  CAS  Google Scholar 

  5. Hughes DE, Salter DM, Simpson R. CD44 expression in human bone: a novel marker of osteocytic differentiation. J Bone Min Res. 1994;9(1):39–44.

    Article  CAS  Google Scholar 

  6. Ohizumi I, Harada N, Taniguchi K, Tsutsumi Y, Nakagawa S, Kaiho S, et al. Association of CD44 with OTS-8 in tumor vascular endothelial cells. Biochim Biophys Acta. 2000;1497(2):197–203.

    Article  CAS  PubMed  Google Scholar 

  7. Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr D, Allen MR, editors. Basic and applied bone biology. 1st ed. Amsterdam: Elsevier Inc.; 2014. p. 27–45.

    Chapter  Google Scholar 

  8. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38(11):1310–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Holmbeck K, Bianco P, Pidoux I, Inoue S, Billinghurst RC, Wu W, et al. The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci. 2005;118(Pt 1):147–56.

    Article  CAS  PubMed  Google Scholar 

  10. Zhao W, Byrne MH, Wang Y, Krane SM. Osteocyte and osteoblast apoptosis and excessive bone deposition accompany failure of collagenase cleavage of collagen. J Clin Invest. 2000;106(8):941–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun L, et al. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Min Res. 2012;27(2):374–89.

    Article  CAS  Google Scholar 

  12. Plotkin LI, Manolagas SC, Bellido T. Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem. 2002;277(10):8648–57.

    Article  CAS  PubMed  Google Scholar 

  13. Bivi N, Lezcano V, Romanello M, Bellido T, Plotkin LI. Connexin43 interacts with barrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone. J Cell Biochem. 2011;112(10):2920–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98(11):6500–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone. 2013;54(2):213–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, et al. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest. 2008;118(2):722–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, et al. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J Biol Chem. 2003;278(3):1998–2007.

    Article  CAS  PubMed  Google Scholar 

  18. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009;24(11):1879–88.

    Article  CAS  PubMed  Google Scholar 

  19. Rowe PS. The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med. 2004;15(5):264–81.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003;285(1):E1–9.

    Article  CAS  PubMed  Google Scholar 

  21. White KE, Evans WE, O'Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–8.

    Article  CAS  Google Scholar 

  22. Van Bezooijen RL, Roelen BA, Visser A, Wee-Pals L, de Wilt E, Karperien M, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199(6):805–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Robling AG, Castillo AB, Turner CH. Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng. 2006;8:455–98.

    Article  CAS  PubMed  Google Scholar 

  24. Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ, Dusevich V, et al. Osteocytes, not osteoblasts or lining cells, are the Main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One. 2015;10(9):e0138189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med. 2011;17(10):1235–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4.

    Article  CAS  PubMed  Google Scholar 

  27. O'Brien CA, Nakashima T, Takayanagi H. Osteocyte control of osteoclastogenesis. Bone. 2013;54(2):258–63.

    Article  CAS  PubMed  Google Scholar 

  28. Delgado-Calle J, Arozamena J, Garcia-Renedo R, Garcia-Ibarbia C, Pascual-Carra MA, Gonzalez-Macias J, et al. Osteocyte deficiency in hip fractures. Calcif Tissue Int. 2011;89(4):327–34.

    Article  CAS  PubMed  Google Scholar 

  29. Dallas SL, Bonewald LF. Dynamics of the transition from osteoblast to osteocyte. Ann N Y Acad Sci. 2010;1192(1):437–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Poole KE, Van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842–4.

    Article  CAS  PubMed  Google Scholar 

  31. Irie K, Ejiri S, Sakakura Y, Shibui T, Yajima T. Matrix mineralization as a trigger for osteocyte maturation. J Histochem Cytochem. 2008;56(6):561–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6(10):e25900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tu X, Delgado-Calle J, Condon KW, Maycas M, Zhang H, Carlesso N, et al. Osteocytes mediate the anabolic actions of canonical Wnt/b-catenin signaling in bone. Proc Natl Acad Sci U S A. 2015;112(5):E478–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Delgado-Calle J, Sato AY, Bellido T. Role and mechanism of action of sclerostin in bone. Bone. 2017;96:29–37.

    Article  CAS  PubMed  Google Scholar 

  35. Bellido T. Osteocyte-Driven Bone Remodeling. Calcif Tissue Int. 2014;94(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  36. Delgado-Calle J, Riancho JA. The role of DNA methylation in common skeletal disorders. Biology (Basel). 2012;1(3):698–713.

    CAS  Google Scholar 

  37. Delgado-Calle J, Garmilla P, Riancho JA. Do epigenetic marks govern bone mass and homeostasis? Curr Genomics. 2012;13(3):252–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Turek-Plewa J, Jagodzinski PP. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett. 2005;10(4):631–47.

    CAS  PubMed  Google Scholar 

  39. Santos-Rosa H, Caldas C. Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer. 2005;41(16):2381–402.

    Article  CAS  PubMed  Google Scholar 

  40. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    Article  CAS  PubMed  Google Scholar 

  41. Hantusch B, Kalt R, Krieger S, Puri C, Kerjaschki D. Sp1/Sp3 and DNA-methylation contribute to basal transcriptional activation of human podoplanin in MG63 versus Saos-2 osteoblastic cells. BMC Mol Biol. 2007;8:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Miao D, Scutt A. Histochemical localization of alkaline phosphatase activity in decalcified bone and cartilage. J Histochem Cytochem. 2002;50(3):333–40.

    Article  CAS  PubMed  Google Scholar 

  43. Delgado-Calle J, Sanudo C, Sanchez-Verde L, Garcia-Renedo RJ, Arozamena J, Riancho JA. Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage. Bone. 2011;49(4):830–8.

    Article  CAS  PubMed  Google Scholar 

  44. Delgado-Calle J, Sanudo C, Bolado A, Fernandez AF, Arozamena J, Pascual-Carra MA, et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res. 2012;27(4):926–37.

    Article  CAS  PubMed  Google Scholar 

  45. Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, et al. Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res. 2007;22(12):1957–67.

    Article  CAS  PubMed  Google Scholar 

  46. Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, et al. Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci U S A. 2012;109(35):14092–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sebastian A, Loots GG. Transcriptional control of Sost in bone. Bone. 2017;96:76–84.

    Article  CAS  PubMed  Google Scholar 

  48. Delgado-Calle J, Sanudo C, Fernandez AF, Garcia-Renedo R, Fraga MF, Riancho JA. Role of DNA methylation in the regulation of the RANKL-OPG system in human bone. Epigenetics. 2012;7(1):83–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jensen ED, Gopalakrishnan R, Westendorf JJ. Regulation of gene expression in osteoblasts. Biofactors. 2010;36(1):25–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cohen-Kfir E, Artsi H, Levin A, Abramowitz E, Bajayo A, Gurt I, et al. Sirt1 is a regulator of bone mass and a repressor of Sost encoding for Sclerostin: a bone formation inhibitor. Endocrinology. 2011;152(12):4514–24.

    Article  CAS  PubMed  Google Scholar 

  51. Wein MN, Liang Y, Goransson O, Sundberg TB, Wang J, Williams EA, et al. SIKs control osteocyte responses to parathyroid hormone. Nat Commun. 2016;7:13176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Luzi E, Marini F, Sala SC, Tognarini I, Galli G, Brandi ML. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. J Bone Miner Res. 2008;23(2):287–95.

    Article  CAS  PubMed  Google Scholar 

  54. Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, et al. A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A. 2009;106(49):20794–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Davis HM, Pacheco-Costa R, Atkinson EG, Brun LR, Gortazar AR, Harris J, et al. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell. 2017;16(3):551–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Noble BS, Peet N, Stevens HY, Brabbs A, Mosley JR, Reilly GC, et al. Mechanical loading: biphasic osteocyte survival and the targeting of osteoclasts for bone destruction in rat cortical bone. Am J Physiol Cell Physiol. 2003;284(4):C934–43.

    Article  CAS  PubMed  Google Scholar 

  57. Bellido T, Plotkin LI. Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone. 2011;49:50–5.

    Article  CAS  PubMed  Google Scholar 

  58. Jilka RL, Bellido T, Almeida M, Plotkin LI, O'Brien CA, Weinstein RS, et al. Apoptosis in bone cells. In: Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology. 3rd. ed. San Diego: Academic Press; 2008. p. 237–61.

    Chapter  Google Scholar 

  59. Tomkinson A, Reeve J, Shaw RW, Noble BS. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab. 1997;82(9):3128–35.

    CAS  PubMed  Google Scholar 

  60. Tomkinson A, Gevers EF, Wit JM, Reeve J, Noble BS. The role of estrogen in the control of rat osteocyte apoptosis. J Bone Min Res. 1998;13(8):1243–50.

    Article  CAS  Google Scholar 

  61. Huber C, Collishaw S, Mosley JR, Reeve J, Noble BS. Selective estrogen receptor modulator inhibits osteocyte apoptosis during abrupt estrogen withdrawal: implications for bone quality maintenance. Calcif Tissue Int. 2007;81(2):139–44.

    Article  CAS  PubMed  Google Scholar 

  62. Mann V, Huber C, Kogianni G, Collins F, Noble B. The antioxidant effect of estrogen and selective estrogen receptor modulators in the inhibition of osteocyte apoptosis in vitro. Bone. 2007;40(3):674–84.

    Article  CAS  PubMed  Google Scholar 

  63. Kousteni S, Chen JR, Bellido T, Han L, Ali AA, O'Brien CA, et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science. 2002;298(5594):843–6.

    Article  CAS  PubMed  Google Scholar 

  64. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001;104(5):719–30.

    CAS  PubMed  Google Scholar 

  65. Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of ERK activation. J Biol Chem. 2005;280(8):7317–25.

    Article  CAS  PubMed  Google Scholar 

  66. Plotkin LI, Han L, Manolagas SC, Bellido T. An ERK-mediated anti-apoptotic effect of bisphosphonates, but not estrogen, on osteocytes in vitro, depends on the integrity of gap junctions: evidence for distinct signaling pathways upstream from ERKs. J. Bone Min. Res. 1999;14(suppl 1):S155.

    Google Scholar 

  67. Jilka RL, Parfitt AM, Manolagas SC, Bellido T, Smith C. Cleavage of collagen by osteoblasts in vitro generates anti-apoptotic signals: a mechanism for the regulation of their functional lifespan and fate during bone formation. J Bone Min Res. 1999;14(suppl 1):S343.

    Google Scholar 

  68. Jilka RL, Takahashi K, Munshi M, Williams DC, Roberson PK, Manolagas SC. Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J Clin Invest. 1998;101(9):1942–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Boyce BF, Xing L, Jilka RL, Bellido T, Weinstein RS, Parfitt AM, et al. Apoptosis in bone cells. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. 2nd ed. San Diego: Academic Press; 2002. p. 151–68.

    Chapter  Google Scholar 

  70. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102(2):274–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Aguirre JI, Plotkin LI, Stewart SA, Weinstein RS, Parfitt AM, Manolagas SC, et al. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Min Res. 2006;21(4):605–15.

    Article  Google Scholar 

  72. Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282(37):27285–97.

    Article  CAS  PubMed  Google Scholar 

  73. Bellido T. Antagonistic interplay between mechanical forces and glucocorticoids in bone: a tale of kinases. J Cell Biochem. 2010;111(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  74. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999;104(10):1363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Plotkin LI, Mathov I, Aguirre JI, Parfitt AM, Manolagas SC, Bellido T. Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases and ERKs. Am J Physiol Cell Physiol. 2005;289:C633–43.

    Article  CAS  PubMed  Google Scholar 

  76. Bakker A, Klein-Nulend J, Burger E. Shear stress inhibits while disuse promotes osteocyte apoptosis. Biochem Biophys Res Commun. 2004;320(4):1163–8.

    Article  CAS  PubMed  Google Scholar 

  77. Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone. 2008;42(4):606–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Armstrong VJ, Muzylak M, Sunters A, Zaman G, Saxon LK, Price JS, et al. Wnt/b-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor a. J Biol Chem. 2007;282(28):20715–27.

    Article  CAS  PubMed  Google Scholar 

  79. Sunters A, Armstrong VJ, Zaman G, Kypta RM, Kawano Y, Lanyon LE, et al. Mechano-transduction in osteoblastic cells involves strain-regulated, estrogen receptor {alpha}-mediated, control of IGF-IR sensitivity to ambient IGF, leading to PI3-K/ AKT dependent, Wnt/LRP5 receptor-independent activation of {beta}-catenin signaling. J Biol Chem. 2010;285(12):8743–58.

    Article  CAS  PubMed  Google Scholar 

  80. Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S. Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem. 2005;280(50):41342–51.

    Article  CAS  PubMed  Google Scholar 

  81. Gortazar AR, Martin-Millan M, Bravo B, Plotkin LI, Bellido T. Crosstalk between caveolin-1/ERKs and ß-catenin survival pathways in osteocyte mechanotransduction. J Biol Chem. 2013;288(12):8168–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Verborgt O, Gibson G, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Min Res. 2000;15(1):60–7.

    Article  CAS  Google Scholar 

  83. Verborgt O, Tatton NA, Majeska RJ, Schaffler MB. Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation? J Bone Miner Res. 2002;17(5):907–14.

    Article  CAS  PubMed  Google Scholar 

  84. Bellido T. Osteocyte apoptosis induces bone resorption and impairs the skeletal response to weightlessness. BoneKEy-osteovision. 2007;4(9):252–6.

    Article  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. Cabahug-Zuckerman P, Frikha-Benayed D, Majeska RJ, Tuthill A, Yakar S, Judex S, et al. Osteocyte apoptosis caused by Hindlimb unloading is required to trigger osteocyte RANKL production and subsequent resorption of cortical and trabecular bone in mice femurs. J Bone Miner Res. 2016;31(7):1356–65.

    Article  CAS  PubMed  Google Scholar 

  87. Kennedy OD, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo. Bone. 2014;64:132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Plotkin LI, de Gortazar AR, Davis HM, Condon KW, Gabilondo H, Maycas M, et al. Inhibition of osteocyte apoptosis prevents the increase in Osteocytic RANKL but it does not stop bone resorption or the loss of bone induced by unloading. J Biol Chem. 2015;290(31):18934–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kramer I, Halleux C, Keller H, Pegurri M, Gooi JH, Weber PB, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 2010;30(12):3071–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yang J, Shah R, Robling AG, Templeton E, Yang H, Tracey KJ, et al. HMGB1 is a bone-active cytokine. J Cell Physiol. 2008;214(3):730–9.

    Article  CAS  PubMed  Google Scholar 

  91. Kennedy OD, Herman BC, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone. 2012;50(5):1115–22.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Marcus R. Mechanisms of exercise effects on bone. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. San Diego: Academic Press; 2002. p. 1477–88.

    Chapter  Google Scholar 

  93. Bikle DD, Halloran BP, Morey-Holton E. Spaceflight and the skeleton: lessons for the earthbound. Gravit Space Biol Bull. 1997;10(2):119–35.

    CAS  PubMed  Google Scholar 

  94. Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, et al. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest. 2003;111(11):1651–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Plotkin LI, Bellido T. Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ERK pathway: a gap junction-independent action of connexin43. Cell Adhes Commun. 2001;8(4–6):377–82.

    Article  CAS  Google Scholar 

  96. Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int. 1995;57(5):344–58.

    Article  CAS  PubMed  Google Scholar 

  97. Burger EH, Klein-Nulend J, Van Der Plas A, Nijweide PJ. Function of osteocytes in bone – their role in mechanotransduction. J Nutr. 1995;125(7 Suppl):2020S–3S.

    Article  CAS  PubMed  Google Scholar 

  98. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179–92.

    Article  CAS  PubMed  Google Scholar 

  99. Delgado-Calle J, Bellido T. Osteocytes and skeletal pathophysiology. Curr Mol Biol Rep. 2015;1(4):157–67.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860–9.

    Article  PubMed  Google Scholar 

  101. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. Chronic elevation of PTH in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. 2005;146(11):4577–83.

    Article  CAS  PubMed  Google Scholar 

  102. Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37(2):148–58.

    Article  CAS  PubMed  Google Scholar 

  103. van Lierop AH, Witteveen J, Hamdy N, Papapoulos S. Patients with primary hyperparathyroidism have lower circulating sclerostin levels than euparathyroid controls. Eur J Endocrinol. 2010;163(5):833–7.

    Article  PubMed  CAS  Google Scholar 

  104. Drake MT, Srinivasan B, Modder UI, Peterson JM, McCready LK, Riggs BL, et al. Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women. J Clin Endocrinol Metab. 2010;95(11):5056–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab. 2010;95(4):1991–7.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2012;50(1):209–17.

    Article  CAS  PubMed  Google Scholar 

  107. Robling AG, Turner CH. Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19(4):319–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chang MK, Kramer I, Huber T, Kinzel B, Guth-Gundel S, Leupin O, et al. Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci U S A. 2014;111(48):E5187–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Witcher PC, Miner SE, Horan DJ, Bullock WA, Lim KE, Kang KS, et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight. 2018;3(11).

    Google Scholar 

  110. Glass DA, Karsenty G. In vivo analysis of Wnt signaling in bone. Endocrinology. 2007;148(6):2630–4.

    Article  CAS  PubMed  Google Scholar 

  111. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature. 2014;506(7487):240–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fujita K, Xing Q, Khosla S, Monroe DG. Mutual enhancement of differentiation of osteoblasts and osteocytes occurs through direct cell-cell contact. J Cell Biochem. 2014;115(11):2039–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Zanotti S, Canalis E. Notch signaling in skeletal health and disease. Eur J Endocrinol. 2013;168(6):R95–R103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Canalis E, Parker K, Feng JQ, Zanotti S. Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology. 2013;154(2):623–34.

    Article  CAS  PubMed  Google Scholar 

  115. Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ, et al. Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun. 2018;9(1):2909.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Harris SE, MacDougall M, Horn D, Woodruff K, Zimmer SN, Rebel VI, et al. Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects. Bone. 2012;50(1):42–53.

    Article  CAS  PubMed  Google Scholar 

  117. Parfitt AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone. 2002;30(1):5–7.

    Article  CAS  PubMed  Google Scholar 

  118. Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab. 2010;21(6):369–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010;31:266–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Weinstein RS, Wan C, Liu Q, Wang Y, Almeida M, O'Brien CA, et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in 21-month-old mice. Aging Cell. 2009;9(2):147–61.

    Article  PubMed  CAS  Google Scholar 

  121. Plotkin LI, Bellido T. Beyond gap junctions: Connexin43 and bone cell signaling. Bone. 2013;52(1):157–66.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang Y, Paul EM, Sathyendra V, Davidson A, Bronson S, Srinivasan S, et al. Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS One. 2011;6(8):e23516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Grimston SK, Brodt MD, Silva MJ, Civitelli R. Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the Connexin43 gene (Gja1). J Bone Miner Res. 2008;23(6):879–86.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Age and distance from the surface but not menopause reduce osteocyte density in human cancellous bone. Bone. 2002;31(2):313–8.

    Article  CAS  PubMed  Google Scholar 

  125. Davis HM, Aref MW, Aguilar-Perez A, Pacheco-Costa R, Allen K, Valdez S, et al. Cx43 overexpression in osteocytes prevents osteocyte apoptosis and preserves cortical bone quality in aging mice. JBMR Plus. 2018; https://doi.org/10.1002/jbm4.10035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sato AY, Peacock M, Bellido T. Glucocorticoid excess in bone and muscle. Clin Rev Bone Miner Metab. 2018;16(1):33–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med. 2011;365(1):62–70.

    Article  CAS  PubMed  Google Scholar 

  128. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001;2(1):65–73.

    Article  CAS  PubMed  Google Scholar 

  129. Aarden EM, Wassenaar AM, Alblas MJ, Nijweide PJ. Immunocytochemical demonstration of extracellular matrix proteins in isolated osteocytes. Histochem Cell Biol. 1996;106(5):495–501.

    Article  CAS  PubMed  Google Scholar 

  130. O'Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology. 2004;145(4):1835–41.

    Article  CAS  PubMed  Google Scholar 

  131. Gohel A, McCarthy MB, Gronowicz G. Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro. Endocrinology. 1999;140(11):5339–47.

    Article  CAS  PubMed  Google Scholar 

  132. Plotkin LI, Manolagas SC, Bellido T. Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival: evidence for inside-out signaling leading to anoikis. J Biol Chem. 2007;282(33):24120–30.

    Article  CAS  PubMed  Google Scholar 

  133. Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest. 2002;109(8):1041–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Necela BM, Cidlowski JA. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc. 2004;1(3):239–46.

    Article  CAS  PubMed  Google Scholar 

  135. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–23.

    Article  CAS  PubMed  Google Scholar 

  136. Druilhe A, Letuve S, Pretolani M. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis. 2003;8(5):481–95.

    Article  CAS  PubMed  Google Scholar 

  137. Limbourg FP, Liao JK. Nontranscriptional actions of the glucocorticoid receptor. J Mol Med. 2003;81(3):168–74.

    Article  CAS  PubMed  Google Scholar 

  138. Chauhan D, Pandey P, Ogata A, Teoh G, Treon S, Urashima M, et al. Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene. 1997;15(7):837–43.

    Article  CAS  PubMed  Google Scholar 

  139. Blaukat A, Ivankovic-Dikic I, Gronroos E, Dolfi F, Tokiwa G, Vuori K, et al. Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades. J Biol Chem. 1999;274(21):14893–901.

    Article  CAS  PubMed  Google Scholar 

  140. Tokiwa G, Dikic I, Lev S, Schlessinger J. Activation of Pyk2 by stress signals and coupling with JNK signaling pathway. Science. 1996;273(5276):792–4.

    Article  CAS  PubMed  Google Scholar 

  141. Chauhan D, Hideshima T, Pandey P, Treon S, Teoh G, Raje N, et al. RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene. 1999;18(48):6733–40.

    Article  CAS  PubMed  Google Scholar 

  142. Xiong W, Parsons JT. Induction of apoptosis after expression of PYK2, a tyrosine kinase structurally related to focal adhesion kinase. J Cell Biol. 1997;139(2):529–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T. Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem. 1995;270(36):21206–19.

    Article  CAS  PubMed  Google Scholar 

  144. Avraham H, Park S, Schinkmann K, Avraham S. RAFTK/Pyk2-mediated cellular signalling. Cell Signal. 2000;12(3):123–33.

    Article  CAS  PubMed  Google Scholar 

  145. Giancotti FG, Ruoslahti E. Integrin signaling. Science. 1999;285(5430):1028–32.

    Article  CAS  PubMed  Google Scholar 

  146. Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science. 1995;268(5208):233–9.

    Article  CAS  PubMed  Google Scholar 

  147. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9(5):701–6.

    Article  CAS  PubMed  Google Scholar 

  148. Ginsberg MH, Partridge A, Shattil SJ. Integrin regulation. Curr Opin Cell Biol. 2005;17(5):509–16.

    Article  CAS  PubMed  Google Scholar 

  149. Hynes R. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87.

    Article  CAS  PubMed  Google Scholar 

  150. Vanden Berghe W, Francesconi E, De Bosscher K, Resche-Rigon M, Haegeman G. Dissociated glucocorticoids with anti-inflammatory potential repress interleukin-6 gene expression by a nuclear factor-kappaB-dependent mechanism. Mol Pharmacol. 1999;56(4):797–806.

    Google Scholar 

  151. Cheng SL, Zhang SF, Mohan S, Lecanda F, Fausto A, Hunt AH, et al. Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone. J Cell Biochem. 1998;71(3):449–58.

    Article  CAS  PubMed  Google Scholar 

  152. Chang DJ, Ji C, Kim KK, Casinghino S, McCarthy TL, Centrella M. Reduction in transforming growth factor beta receptor I expression and transcription factor CBFa1 on bone cells by glucocorticoid. J Biol Chem. 1998;273(9):4892–6.

    Article  CAS  PubMed  Google Scholar 

  153. Doherty WJ, Derome ME, McCarthy MB, Gronowicz GA. The effect of glucocorticoids on osteoblast function. The effect of corticosterone on osteoblast expression of beta 1 integrins. J Bone Joint Surg Am. 1995;77(3):396–404.

    Article  CAS  PubMed  Google Scholar 

  154. Almeida M, Han L, Ambrogini E, Weinstein RS, Manolagas SC. Glucocorticoids and tumor necrosis factor (TNF) alpha increase oxidative stress and suppress WNT signaling in osteoblasts. J Biol Chem. 2011;286(52):44326–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619–33.

    Article  CAS  PubMed  Google Scholar 

  156. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.

    Article  CAS  PubMed  Google Scholar 

  157. Sato AY, Tu X, McAndrews KA, Plotkin LI, Bellido T. Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice. Bone. 2015;73:60–8.

    Article  PubMed  CAS  Google Scholar 

  158. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005;307(5711):935–9.

    Article  CAS  PubMed  Google Scholar 

  159. Tsaytler P, Harding HP, Ron D, Bertolotti A. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science. 2011;332(6025):91–4.

    Article  CAS  PubMed  Google Scholar 

  160. Yokota H, Hamamura K, Chen A, Dodge TR, Tanjung N, Abedinpoor A, et al. Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells. BMC Musculoskelet Disord. 2013;14:197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hamamura K, Tanjung N, Yokota H. Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha. J Bone Miner Metab. 2013;31(6):618–28.

    Article  CAS  PubMed  Google Scholar 

  162. Hamamura K, Yokota H. Stress to endoplasmic reticulum of mouse osteoblasts induces apoptosis and transcriptional activation for bone remodeling. FEBS Lett. 2007;581(9):1769–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, et al. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011;286(6):4809–18.

    Article  CAS  PubMed  Google Scholar 

  164. Sato AY, Cregor M, Delgado-Calle J, Condon KW, Allen MR, Peacock M, et al. Protection from glucocorticoid-induced osteoporosis by anti-catabolic signaling in the absence of Sost/sclerostin. J Bone Miner Res. 2016;31(10):1791–802.

    Article  CAS  PubMed  Google Scholar 

  165. Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007;40(6):1434–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kim SW, Pajevic PD, Selig M, Barry KJ, Yang JY, Shin CS, et al. Intermittent PTH administration converts quiescent lining cells to active osteoblasts. J Bone Miner Res. 2012;27(10):2075–84.

    Article  CAS  PubMed  Google Scholar 

  167. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev. 2005;26(5):688–703.

    Article  CAS  PubMed  Google Scholar 

  168. Rhee Y, Lee EY, Lezcano V, Ronda AC, Condon KW, Allen MR, et al. Resorption controls bone anabolism driven by PTH receptor signaling in osteocytes. J Biol Chem. 2013;288(41):29809–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Bellido T, Saini V, Divieti Pajevic P. Effects of PTH on osteocyte function. Bone. 2013;54(2):250–7.

    Article  CAS  PubMed  Google Scholar 

  170. Wein MN. Parathyroid hormone signaling in osteocytes. JBMR Plus. 2018;2(1):22–30.

    Article  CAS  PubMed  Google Scholar 

  171. Yang M, Trettel LB, Adams DJ, Harrison JR, Canalis E, Kream BE. Col3.6-HSD2 transgenic mice: a glucocorticoid loss-of-function model spanning early and late osteoblast differentiation. Bone. 2010;47(3):573–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010;299(4):F882–9.

    Article  CAS  PubMed  Google Scholar 

  173. O'Brien CA, Plotkin LI, Galli C, Goellner J, Gortazar AR, Allen MR, et al. Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One. 2008;3(8):e2942.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, et al. PTH receptor signaling in osteocytes governs periosteal bone formation and intra-cortical remodeling. J Bone Miner Res. 2011;26(5):1035–46.

    Article  CAS  PubMed  Google Scholar 

  175. Rhee Y, Bivi N, Farrow EG, Lezcano V, Plotkin LI, White KE, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49(4):636–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Delgado-Calle J, Tu X, Pacheco-Costa R, McAndrews K, Edwards R, Pellegrini G, 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.

    Article  CAS  PubMed  Google Scholar 

  177. Saini V, Marengi DA, Barry KJ, Fulzele KS, Heiden E, Liu X, et al. Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. J Biol Chem. 2013;288(28):20122–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Tawfeek H, Bedi B, Li JY, Adams J, Kobayashi T, Weitzmann MN, et al. Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PLoS One. 2010;5(8):e12290.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Gao Y, Wu X, Terauchi M, Li JY, Grassi F, Galley S, et al. T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 2008;8(2):132–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Li JY, Yu M, Tyagi AM, Vaccaro C, Hsu E, Adams J, et al. IL-17 receptor signaling in osteoblasts/osteocytes mediates PTH-induced bone loss and enhances Osteocytic RANKL production. J Bone Miner Res. 2019;34(2):349–60.

    Article  CAS  PubMed  Google Scholar 

  181. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MJ, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283(9):5866–75.

    Article  CAS  PubMed  Google Scholar 

  182. Ben-Awadh A, Delgado-Calle J, Tu X, Kuhlenschmidt K, Allen MR, Plotkin LI, et al. Parathyroid hormone receptor signaling induces bone resorption in the adult skeleton by directly regulating the RANKL gene in osteocytes. Endocrinology. 2014;155(8):2797–809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Delgado-Calle J, Hancock B, Likine EF, Sato AY, McAndrews K, Sanudo C, et al. MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production. FASEB J. 2018;32(5):2878–90.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis. Osteoporos Int. 2007;18(4):427–44.

    Article  CAS  PubMed  Google Scholar 

  185. Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res. 2007;22(9):1317–28.

    Article  CAS  PubMed  Google Scholar 

  186. Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep. 2015;13(5):327–35.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Maycas M, McAndrews KA, Sato AY, Pellegrini GG, Brown DM, Allen MR, et al. PTHrP-derived peptides restore bone mass and strength in diabetic mice: additive effect of mechanical loading. J Bone Miner Res. 2016;32(6):486–97.

    PubMed  Google Scholar 

  188. Motyl KJ, McCauley LK, McCabe LR. Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol. 2012;227(4):1326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Brun J, Berthou F, Trajkovski M, Maechler P, Foti M, Bonnet N. Bone regulates browning and energy metabolism through mature osteoblast/osteocyte PPARgamma expression. Diabetes. 2017;66(10):2541–54.

    Article  CAS  PubMed  Google Scholar 

  190. Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer. 2016;16(6):373–86.

    Article  CAS  PubMed  Google Scholar 

  191. Delgado-Calle J. Osteocytes and their messengers as targets for the treament of multiple myeloma. Clin Rev Bone Min Metab. 2017;15(1):49–56.

    Article  Google Scholar 

  192. Delgado-Calle J, Bellido T, Roodman GD. Role of osteocytes in multiple myeloma bone disease. Curr Opin Support Palliat Care. 2014;8(4):407–13.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Giuliani N, Ferretti M, Bolzoni M, Storti P, Lazzaretti M, Dalla PB, et al. Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation. Leukemia. 2012;26(6):1391–401.

    Article  CAS  PubMed  Google Scholar 

  194. Delgado-Calle J, Anderson J, Cregor MD, Hiasa M, Chirgwin JM, Carlesso N, et al. Bidirectional notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Res. 2016;76(5):1089–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Toscani D, Palumbo C, Dalla PB, Ferretti M, Bolzoni M, Marchica V, et al. The proteasome inhibitor Bortezomib maintains osteocyte viability in multiple myeloma patients by reducing both apoptosis and autophagy: a new function for proteasome inhibitors. J Bone Miner Res. 2016;31(4):815–27.

    Article  CAS  PubMed  Google Scholar 

  196. McDonald MM, Delgado-Calle J. Sclerostin: an emerging target for the treatment of Cancer-induced bone disease. Curr Osteoporos Rep. 2017;15(6):532–41.

    Article  PubMed  Google Scholar 

  197. Zhu M, Liu C, Li S, Zhang S, Yao Q, Song Q. Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer. Sci Rep. 2017;7(1):11399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Delgado-Calle J, Anderson J, Cregor MD, Condon KW, Kuhstoss SA, Plotkin LI, et al. Genetic deletion of sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth. Leukemia. 2017; https://doi.org/10.1038/leu.2017.152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. McDonald MM, Reagan MR, Youlten SE, Mohanty ST, Seckinger A, Terry RL, et al. Inhibiting the osteocyte specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood. 2017; https://doi.org/10.1182/blood-2017-03-773341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, et al. Regulation of Sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. J Bone Miner Res. 2016;31(6):1225–34.

    Article  CAS  PubMed  Google Scholar 

  201. Sottnik JL, Dai J, Zhang H, Campbell B, Keller ET. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res. 2015;75(11):2151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Sottnik JL, Campbell B, Mehra R, Behbahani-Nejad O, Hall CL, Keller ET. Osteocytes serve as a progenitor cell of osteosarcoma. J Cell Biochem. 2014;115(8):1420–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Hiasa M, Okui T, Allette YM, Ripsch MS, Sun-Wada GH, Wakabayashi H, et al. Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. Cancer Res. 2017;77(6):1283–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Karsenty G, Olson EN. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell. 2016;164(6):1248–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017;543(7645):385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Ferron M, Lacombe J. Regulation of energy metabolism by the skeleton: osteocalcin and beyond. Arch Biochem Biophys. 2014;561:137–46.

    Article  CAS  PubMed  Google Scholar 

  207. Sato M, Asada N, Kawano Y, Wakahashi K, Minagawa K, Kawano H, et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab. 2013;18(5):749–58.

    Article  CAS  PubMed  Google Scholar 

  208. Jansson JO, Palsdottir V, Hagg DA, Schele E, Dickson SL, Anesten F, et al. Body weight homeostat that regulates fat mass independently of leptin in rats and mice. Proc Natl Acad Sci U S A. 2018;115(2):427–32.

    Article  CAS  PubMed  Google Scholar 

  209. Ukita M, Yamaguchi T, Ohata N, Tamura M. Sclerostin enhances adipocyte differentiation in 3T3-L1 cells. J Cell Biochem. 2016;117(6):1419–28.

    Article  CAS  PubMed  Google Scholar 

  210. Fairfield H, Falank C, Harris E, DeMambro V, McDonald M, Pettit JA, et al. The skeletal cell-derived molecule Sclerostin drives bone marrow Adipogenesis. J Cell Physiol. 2017; https://doi.org/10.1002/jcp.25976.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Chandra A, Lin T, Young T, Tong W, Ma X, Tseng WJ, et al. Suppression of Sclerostin alleviates radiation-induced bone loss by protecting bone-forming cells and their progenitors through distinct mechanisms. J Bone Miner Res. 2017;32(2):360–72.

    Article  CAS  PubMed  Google Scholar 

  212. Kim SP, Frey JL, Li Z, Kushwaha P, Zoch ML, Tomlinson RE, et al. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci U S A. 2017;114(52):E11238–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Nelson JH, Davis HM, McAndrews K, Cregor MD, Thompson WR, Plotkin LI, et al. Sclerostin regulates adipocyte fate and mediates paracrine and endocrine signaling between osteocytes and fat. ASBMR annual meeting 2018; Montreal.

    Google Scholar 

  214. Garcia-Martin A, Rozas-Moreno P, Reyes-Garcia R, Morales-Santana S, Garcia-Fontana B, Garcia-Salcedo JA, et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(1):234–41.

    Article  CAS  PubMed  Google Scholar 

  215. Urano T, Shiraki M, Ouchi Y, Inoue S. Association of circulating sclerostin levels with fat mass and metabolic disease--related markers in Japanese postmenopausal women. J Clin Endocrinol Metab. 2012;97(8):E1473–7.

    Article  CAS  PubMed  Google Scholar 

  216. Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab. 2012;97(1):148–54.

    Article  CAS  PubMed  Google Scholar 

  217. Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, et al. LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab. 2015;21(2):262–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. 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.

    Article  CAS  PubMed  Google Scholar 

  219. Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone. 2006;39(3):443–52.

    Article  CAS  PubMed  Google Scholar 

  220. Plotkin LI, Bivi N, Bellido T. A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice. Bone. 2011;49:122–7.

    Article  CAS  PubMed  Google Scholar 

  221. Appelman-Dijkstra NM, Papapoulos SE. Sclerostin inhibition in the management of osteoporosis. Calcif Tissue Int. 2016;98(4):370–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Padhi D, Allison M, Kivitz AJ, Gutierrez MJ, Stouch B, Wang C, et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol. 2014;54(2):168–78.

    Article  CAS  PubMed  Google Scholar 

  223. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19–26.

    Article  CAS  PubMed  Google Scholar 

  224. Recknor CP, Recker RR, Benson CT, Robins DA, Chiang AY, Alam J, et al. The effect of discontinuing treatment with Blosozumab: follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density. J Bone Miner Res. 2015;30(9):1717–25.

    Article  CAS  PubMed  Google Scholar 

  225. Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–27.

    Article  CAS  PubMed  Google Scholar 

  226. Lewiecki EM, Blicharski T, Goemaere S, Lippuner K, Meisner PD, Miller PD, et al. A phase 3 randomized placebo-controlled trial to evaluate efficacy and safety of Romosozumab in men with osteoporosis. J Clin Endocrinol Metab. 2018;103(9):3183–93.

    Article  PubMed  Google Scholar 

  227. Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun. 2016;7:11505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. McClung MR. Emerging therapies for osteoporosis. Endocrinol Metab (Seoul). 2015;30(4):429–35.

    Article  CAS  Google Scholar 

  229. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–31.

    Article  CAS  PubMed  Google Scholar 

  230. Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension study. Osteoporos Int. 2015;26(12):2773–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. 2017;28(5):1723–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Raje N, Terpos E, Willenbacher W, Shimizu K, Garcia-Sanz R, Durie B, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370–81.

    Article  CAS  PubMed  Google Scholar 

  233. Konstantinova IM, Tsimokha AS, Mittenberg AG. Role of proteasomes in cellular regulation. Int Rev Cell Mol Biol. 2008;267:59–124.

    Article  PubMed  CAS  Google Scholar 

  234. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Mukherjee S, Raje N, Schoonmaker JA, Liu JC, Hideshima T, Wein MN, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest. 2008;118(2):491–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Accardi F, Toscani D, Costa F, Aversa F, Giuliani N. The proteasome and myeloma-associated bone disease. Calcif Tissue Int. 2018;102(2):210–26.

    Article  CAS  PubMed  Google Scholar 

  237. Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E, et al. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer. 2012;131(6):1466–71.

    Article  CAS  PubMed  Google Scholar 

  238. Canalis E, Bridgewater D, Schilling L, Zanotti S. Canonical notch activation in osteocytes causes osteopetrosis. Am J Physiol Endocrinol Metab. 2016;310(2):E171–82.

    Article  PubMed  Google Scholar 

  239. Canalis E, Schilling L, Zanotti S. Effects of sex and notch signaling on the osteocyte cell Pool. J Cell Physiol. 2017;232(2):363–70.

    Article  CAS  PubMed  Google Scholar 

  240. Liu P, Ping Y, Ma M, Zhang D, Liu C, Zaidi S, et al. Anabolic actions of notch on mature bone. Proc Natl Acad Sci U S A. 2016;113(15):E2152–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Zanotti S, Canalis E. Parathyroid hormone inhibits notch signaling in osteoblasts and osteocytes. Bone. 2017;103:159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Delgado-Calle J, Nelson JH, Olson ME, McAndrews K, Atkinson EG, Tu X, et al. Anabolic PTH signaling activates the canonical Notch pathway in osteocytes to restrain bone resorption and facilitate bone gain. ASBMR 2017 annual meeting 2017; Denver.

    Google Scholar 

  243. Delgado-Calle J, Wu G, Olson ME, McAndrews K, Nelson JH, Daniel AL, et al. Bone-targeted pharmacological inhibition of Notch signaling potentiates PTH-induced bone gain. ASBMR 2018 annual meeting 2018; Montreal.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Teresita Bellido .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Delgado-Calle, J., Bellido, T. (2020). Basic Aspects of Osteocyte Function. In: Leder, B., Wein, M. (eds) Osteoporosis. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-319-69287-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-69287-6_3

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-319-69286-9

  • Online ISBN: 978-3-319-69287-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics