1932

Abstract

Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis and the Sost/Dkk1/Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.

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2020-02-10
2024-03-29
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Literature Cited

  1. 1. 
    Smith MM, Hall BK. 1990. Development and evolutionary origins of vertebrate skeletogenic and odontogenic tissues. Biol. Rev. Camb. Philos. Soc. 65:277–373
    [Google Scholar]
  2. 2. 
    Pawlicki R. 1975. Studies of the fossil dinosaur bone in the scanning electron microscope. Z. Mikrosk. Anat. Forsch. 89:393–98
    [Google Scholar]
  3. 3. 
    Schweitzer MH, Zheng W, Cleland TP, Bern M 2013. Molecular analyses of dinosaur osteocytes support the presence of endogenous molecules. Bone 52:414–23
    [Google Scholar]
  4. 4. 
    von Recklinghausen F. 1910. Untersuchungen über Rachitis und Osteomalacia Jena, Ger.: Gustav Fischer
  5. 5. 
    Bélanger LF. 1969. Osteocytic osteolysis. Calcif. Tissue Res. 4:1–12
    [Google Scholar]
  6. 6. 
    Lanyon LE. 1993. Osteocytes, strain detection, bone modeling and remodeling. Calcif. Tissue Int. 53:S102–6
    [Google Scholar]
  7. 7. 
    Van Der Plas A, Aarden EM, Feijen JH, de Boer AH, Wiltink A et al. 1994. Characteristics and properties of osteocytes in culture. J. Bone Miner. Res. 9:1697–704
    [Google Scholar]
  8. 8. 
    Mikuni-Takagaki Y, Kakai Y, Satoyoshi M, Kawano E, Suzuki Y et al. 1995. Matrix mineralization and the differentiation of osteocyte-like cells in culture. J. Bone Miner. Res. 10:231–42
    [Google Scholar]
  9. 9. 
    Mikuni-Takagaki Y, Suzuki Y, Kawase T, Saito S 1996. Distinct responses of different populations of bone cells to mechanical stress. Endocrinology 137:2028–35
    [Google Scholar]
  10. 10. 
    Manolagas SC. 2000. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21:115–37
    [Google Scholar]
  11. 11. 
    Dallas SL, Veno PA. 2012. Live imaging of bone cell and organ cultures. Methods Mol. Biol. 816:425–57
    [Google Scholar]
  12. 12. 
    Tanaka-Kamioka K, Kamioka H, Ris H 1998. Osteocyte shape is dependent on actin filaments and osteocyte processes are unique actin‐rich projections. J. Bone Miner. Res. 10:1555–68
    [Google Scholar]
  13. 13. 
    Verborgt O, Gibson GJ, Schaffler MB 2000. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J. Bone Miner. Res. 15:60–67
    [Google Scholar]
  14. 14. 
    Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA 2011. Matrix-embedded cells control osteoclast formation. Nat. Med. 17:1235–41
    [Google Scholar]
  15. 15. 
    Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M et al. 2011. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17:1231–34
    [Google Scholar]
  16. 16. 
    Yao W, Dai W, Jiang JX, Lane NE 2013. Glucocorticoids and osteocyte autophagy. Bone 54:279–84
    [Google Scholar]
  17. 17. 
    Tate MLK, Adamson JR, Tami AE, Bauer TW 2004. The osteocyte. Int. J. Biochem. Cell Biol. 36:1–8
    [Google Scholar]
  18. 18. 
    Jilka RL, O'Brien CA. 2016. The role of osteocytes in age-related bone loss. Curr. Osteoporos. Rep. 14:16–25
    [Google Scholar]
  19. 19. 
    Boskey AL, Coleman R. 2010. Aging and bone. J. Dent. Res. 89:1333–48
    [Google Scholar]
  20. 20. 
    Tiede-Lewis LM, Xie Y, Hulbert MA, Campos R, Dallas MR et al. 2017. Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. Aging 9:2190–208
    [Google Scholar]
  21. 21. 
    Kobayashi K, Nojiri H, Saita Y, Morikawa D, Ozawa Y et al. 2015. Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. Sci. Rep. 5:9148
    [Google Scholar]
  22. 22. 
    Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB et al. 2016. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31:1920–29
    [Google Scholar]
  23. 23. 
    Kato Y, Windle JJ, Koop BA, Mundy GR, Bonewald LF 1997. Establishment of an osteocyte-like cell line, MLO-Y4. J. Bone Miner. Res. 12:2014–23
    [Google Scholar]
  24. 24. 
    Bodine PV, Vernon SK, Komm BS 1996. Establishment and hormonal regulation of a conditionally transformed preosteocytic cell line from adult human bone. Endocrinology 137:4592–604
    [Google Scholar]
  25. 25. 
    Kato Y, Boskey A, Spevak L, Dallas M, Hori M, Bonewald LF 2001. Establishment of an osteoid preosteocyte-like cell MLO-A5 that spontaneously mineralizes in culture. J. Bone Miner. Res. 16:1622–33
    [Google Scholar]
  26. 26. 
    Barragan-Adjemian C, Nicolella D, Dusevich V, Dallas MR, Eick JD, Bonewald LF 2006. Mechanism by which MLO-A5 late osteoblasts/early osteocytes mineralize in culture: similarities with mineralization of lamellar bone. Calcif. Tissue Int. 79:340–53
    [Google Scholar]
  27. 27. 
    Woo SM, Rosser J, Dusevich V, Kalajzic I, Bonewald LF 2011. Cell line IDG-SW3 replicates osteoblast-to-late-osteocyte differentiation in vitro and accelerates bone formation in vivo. J. Bone Miner. Res. 26:2634–46
    [Google Scholar]
  28. 28. 
    Spatz JM, Wein MN, Gooi JH, Qu Y, Garr JL et al. 2015. The Wnt inhibitor sclerostin is up-regulated by mechanical unloading in osteocytes in vitro. J. Biol. Chem. 290:16744–58
    [Google Scholar]
  29. 29. 
    Kalajzic I, Braut A, Guo D, Jiang X, Kronenberg MS et al. 2004. Dentin matrix protein 1 expression during osteoblastic differentiation, generation of an osteocyte GFP-transgene. Bone 35:74–82
    [Google Scholar]
  30. 30. 
    Wang K, Le L, Chun BM, Tiede-Lewis LAM, Shiflett LA et al. 2019. A novel osteogenic cell line that differentiates into GFP-tagged osteocytes and forms mineral with a bone-like lacunocanalicular structure. J. Bone Miner. Res. 34:979–95
    [Google Scholar]
  31. 31. 
    Lu Y, Xie Y, Zhang S, Dusevich V, Bonewald LF, Feng JQ 2007. DMP1-targeted Cre expression in odontoblasts and osteocytes. J. Dent. Res. 86:320–25
    [Google Scholar]
  32. 32. 
    Kalajzic I, Kalajzic Z, Kaliterna M, Gronowicz G, Clark SH et al. 2002. Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J. Bone Miner. Res. 17:15–25
    [Google Scholar]
  33. 33. 
    Powell WF Jr., Barry KJ, Tulum I, Kobayashi T, Harris SE et al. 2011. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J. Endocrinol. 209:21–32
    [Google Scholar]
  34. 34. 
    Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ et al. 2015. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLOS ONE 10:e0138189
    [Google Scholar]
  35. 35. 
    Maurel DB, Matsumoto T, Vallejo JA, Johnson ML, Dallas SL et al. 2019. Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes. Bone Res 7:6
    [Google Scholar]
  36. 36. 
    Webster DJ, Schneider P, Dallas SL, Muller R 2013. Studying osteocytes within their environment. Bone 54:285–95
    [Google Scholar]
  37. 37. 
    Genthial R, Beaurepaire E, Schanne-Klein MC, Peyrin F, Farlay D et al. 2017. Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy. Sci. Rep. 7:3419
    [Google Scholar]
  38. 38. 
    Kamel-ElSayed SA, Tiede-Lewis LM, Lu Y, Veno PA, Dallas SL 2015. Novel approaches for two and three dimensional multiplexed imaging of osteocytes. Bone 76:129–40
    [Google Scholar]
  39. 39. 
    Ishihara Y, Sugawara Y, Kamioka H, Kawanabe N, Kurosaka H et al. 2012. In situ imaging of the autonomous intracellular Ca2+ oscillations of osteoblasts and osteocytes in bone. Bone 50:842–52
    [Google Scholar]
  40. 40. 
    Dallas SL, Veno PA, Rosser JL, Barragan-Adjemian C, Rowe DW et al. 2009. Time lapse imaging techniques for comparison of mineralization dynamics in primary murine osteoblasts and the late osteoblast/early osteocyte-like cell line MLO-A5. Cells Tissues Organs 189:6–11
    [Google Scholar]
  41. 41. 
    Tanaka T, Hoshijima M, Sunaga J, Nishida T, Hashimoto M et al. 2018. Analysis of Ca2+ response of osteocyte network by three-dimensional time-lapse imaging in living bone. J. Bone Miner. Metab. 36:519–28
    [Google Scholar]
  42. 42. 
    Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jahn K et al. 2012. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J. Bone Miner. Res. 27:1018–29
    [Google Scholar]
  43. 43. 
    Buenzli PR, Sims NA. 2015. Quantifying the osteocyte network in the human skeleton. Bone 75:144–50
    [Google Scholar]
  44. 44. 
    Jahn K, Kelkar S, Zhao H, Xie Y, Tiede-Lewis LM et al. 2017. Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. J. Bone Miner. Res. 32:1761–72
    [Google Scholar]
  45. 45. 
    Wysolmerski JJ. 2013. Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 54:230–36
    [Google Scholar]
  46. 46. 
    Rodionova NV, Oganov VS, Zolotova NV 2002. Ultrastructural changes in osteocytes in microgravity conditions. Adv. Space Res. 30:765–70
    [Google Scholar]
  47. 47. 
    Blaber EA, Dvorochkin N, Lee C, Alwood JS, Yousuf R et al. 2013. Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLOS ONE 8:e61372
    [Google Scholar]
  48. 48. 
    Zallone AZ, 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]
  49. 49. 
    Kogawa M, Wijenayaka AR, Ormsby RT, Thomas GP, Anderson PH et al. 2013. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J. Bone Miner. Res. 28:2436–48
    [Google Scholar]
  50. 50. 
    Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF 2018. Physiological and pathological osteocytic osteolysis. J. Musculoskelet. Neuronal Interact. 18:292–303
    [Google Scholar]
  51. 51. 
    Lane NE, Yao W, Balooch M, Nalla RK, Balooch G et al. 2006. Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J. Bone Miner. Res. 21:466–76
    [Google Scholar]
  52. 52. 
    Tokarz D, Martins JS, Petit ET, Lin CP, Demay MB, Liu ES 2018. Hormonal regulation of osteocyte perilacunar and canalicular remodeling in the Hyp mouse model of X-linked hypophosphatemia. J. Bone Miner. Res. 33:499–509
    [Google Scholar]
  53. 53. 
    Wolff J. 1892. Das Gesetz der Transformen der Knochen Berlin: A. Hirschwald
  54. 54. 
    Frost HM. 1960. Measurement of osteocytes per unit volume and volume components of osteocytes and canaliculae in man. Henry Ford Hosp. Med. Bull. 8:208–11
    [Google Scholar]
  55. 55. 
    Klein-Nulend J, Semeins CM, Ajubi NE, Nijweide PJ, Burger EH 1995. Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts—correlation with prostaglandin upregulation. Biochem. Biophys. Res. Commun. 217:640–48
    [Google Scholar]
  56. 56. 
    Klein-Nulend J, van der Plas A, Semeins CM, Ajubi NE, Frangos JA et al. 1995. Sensitivity of osteocytes to biomechanical stress in vitro. FASEB J 9:441–45
    [Google Scholar]
  57. 57. 
    Kamel MA, Picconi JL, Lara-Castillo N, Johnson ML 2010. Activation of β-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: implications for the study of mechanosensation in bone. Bone 47:872–81
    [Google Scholar]
  58. 58. 
    Lu XL, Huo B, Chiang V, Guo XE 2012. Osteocytic network is more responsive in calcium signaling than osteoblastic network under fluid flow. J. Bone Miner. Res. 27:563–74
    [Google Scholar]
  59. 59. 
    Burra S, Nicolella DP, Francis WL, Freitas CJ, Mueschke NJ et al. 2010. Dendritic processes of osteocytes are mechanotransducers that induce the opening of hemichannels. PNAS 107:13648–53
    [Google Scholar]
  60. 60. 
    Adachi T, Aonuma Y, Tanaka M, Hojo M, Takano-Yamamoto T, Kamioka H 2009. Calcium response in single osteocytes to locally applied mechanical stimulus: differences in cell process and cell body. J. Biomech. 42:1989–95
    [Google Scholar]
  61. 61. 
    Palumbo C, Ferretti M, Marotti G 2004. Osteocyte dendrogenesis in static and dynamic bone formation: an ultrastructural study. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 278:474–80
    [Google Scholar]
  62. 62. 
    Grimston SK, Watkins MP, Brodt MD, Silva MJ, Civitelli R 2012. Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice. PLOS ONE 7:e44222
    [Google Scholar]
  63. 63. 
    Grimston SK, Screen J, Haskell JH, Chung DJ, Brodt MD et al. 2006. Role of connexin43 in osteoblast response to physical load. Ann. N. Y. Acad. Sci. 1068:214–24
    [Google Scholar]
  64. 64. 
    Siller-Jackson AJ, Burra S, Gu S, Xia X, Bonewald LF et al. 2008. Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading. J. Biol. Chem. 283:26374–82
    [Google Scholar]
  65. 65. 
    Litzenberger JB, Kim JB, Tummala P, Jacobs CR 2010. β1 Integrins mediate mechanosensitive signaling pathways in osteocytes. Calcif. Tissue Int. 86:325–32
    [Google Scholar]
  66. 66. 
    Watabe H, Furuhama T, Tani-Ishii N, Mikuni-Takagaki Y 2011. Mechanotransduction activates α5β1 integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp. Cell Res. 317:2642–49
    [Google Scholar]
  67. 67. 
    Phillips JA, Almeida EA, Hill EL, Aguirre JI, Rivera MF et al. 2008. Role for β1 integrins in cortical osteocytes during acute musculoskeletal disuse. Matrix Biol 27:609–18
    [Google Scholar]
  68. 68. 
    Lyons JS, Joca HC, Law RA, Williams KM, Kerr JP et al. 2017. Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes. Sci. Signal 10:eaan5748
    [Google Scholar]
  69. 69. 
    Mizoguchi F, Mizuno A, Hayata T, Nakashima K, Heller S et al. 2008. Transient receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. J. Cell. Physiol. 216:47–53
    [Google Scholar]
  70. 70. 
    Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ 2007. Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J. Cell. Physiol. 212:207–14
    [Google Scholar]
  71. 71. 
    Zhang JN, Zhao Y, Liu C, Han ES, Yu X et al. 2015. The role of the sphingosine-1-phosphate signaling pathway in osteocyte mechanotransduction. Bone 79:71–78
    [Google Scholar]
  72. 72. 
    McGarry JG, Klein-Nulend J, Prendergast PJ 2005. The effect of cytoskeletal disruption on pulsatile fluid flow-induced nitric oxide and prostaglandin E2 release in osteocytes and osteoblasts. Biochem. Biophys. Res. Commun. 330:341–48
    [Google Scholar]
  73. 73. 
    Klein-Nulend J, van Oers RF, Bakker AD, Bacabac RG 2014. Nitric oxide signaling in mechanical adaptation of bone. Osteoporos. Int. 25:1427–37
    [Google Scholar]
  74. 74. 
    Bakker AD, Silva VC, Krishnan R, Bacabac RG, Blaauboer ME et al. 2009. Tumor necrosis factor α and interleukin-1β modulate calcium and nitric oxide signaling in mechanically stimulated osteocytes. Arthritis Rheum 60:3336–45
    [Google Scholar]
  75. 75. 
    Vatsa A, Smit TH, Klein-Nulend J 2007. Extracellular NO signalling from a mechanically stimulated osteocyte. J Biomech 40:Suppl. 1S89–95
    [Google Scholar]
  76. 76. 
    Inoue M, Ono T, Kameo Y, Sasaki F, Ono T et al. 2019. Forceful mastication activates osteocytes and builds a stout jawbone. Sci. Rep. 9:4404
    [Google Scholar]
  77. 77. 
    Tian F, Wang Y, Bikle DD 2018. IGF-1 signaling mediated cell-specific skeletal mechano-transduction. J. Orthop. Res. 36:576–83
    [Google Scholar]
  78. 78. 
    Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H 2013. Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading. Bone 54:35–43
    [Google Scholar]
  79. 79. 
    Javaheri B, Stern AR, Lara N, Dallas M, Zhao H et al. 2014. Deletion of a single β-catenin allele in osteocytes abolishes the bone anabolic response to loading. J. Bone Miner. Res. 29:705–15
    [Google Scholar]
  80. 80. 
    Kang KS, Hong JM, Robling AG 2016. Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation. Bone 88:138–45
    [Google Scholar]
  81. 81. 
    Tu X, Rhee Y, Condon KW, Bivi N, Allen MR et al. 2012. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 50:209–17
    [Google Scholar]
  82. 82. 
    Broudy VC, Kaushansky K, Shoemaker SG, Aggarwal BB, Adamson JW 1990. Muramyl dipeptide induces production of hemopoietic growth factors in vivo by a mechanism independent of tumor necrosis factor. J. Immunol. 144:3789–94
    [Google Scholar]
  83. 83. 
    Saxon LK, Jackson BF, Sugiyama T, Lanyon LE, Price JS 2011. Analysis of multiple bone responses to graded strains above functional levels, and to disuse, in mice in vivo show that the human Lrp5 G171V High Bone Mass mutation increases the osteogenic response to loading but that lack of Lrp5 activity reduces it. Bone 49:184–93
    [Google Scholar]
  84. 84. 
    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:E751–58
    [Google Scholar]
  85. 85. 
    Smalt R, Mitchell FT, Howard RL, Chambers TJ 1997. Mechanotransduction in bone cells: induction of nitric oxide and prostaglandin synthesis by fluid shear stress, but not by mechanical strain. Adv. Exp. Med. Biol. 433:311–14
    [Google Scholar]
  86. 86. 
    Han Y, Cowin SC, Schaffler MB, Weinbaum S 2004. Mechanotransduction and strain amplification in osteocyte cell processes. PNAS 101:16689–94
    [Google Scholar]
  87. 87. 
    Verbruggen SW, McGarrigle MJ, Haugh MG, Voisin MC, McNamara LM 2015. Altered mechanical environment of bone cells in an animal model of short- and long-term osteoporosis. Biophys. J. 108:1587–98
    [Google Scholar]
  88. 88. 
    Bonivtch AR, Bonewald LF, Nicolella DP 2007. Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J. Biomech. 40:2199–206
    [Google Scholar]
  89. 89. 
    Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J 2006. Osteocyte lacunae tissue strain in cortical bone. J. Biomech. 39:1735–43
    [Google Scholar]
  90. 90. 
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E et al. 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–23
    [Google Scholar]
  91. 91. 
    Honma M, Ikebuchi Y, Kariya Y, Hayashi M, Hayashi N et al. 2013. RANKL subcellular trafficking and regulatory mechanisms in osteocytes. J. Bone Miner. Res. 28:1936–49
    [Google Scholar]
  92. 92. 
    Aoki S, Honma M, Kariya Y, Nakamichi Y, Ninomiya T et al. 2010. Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis. J. Bone Miner. Res. 25:1907–21
    [Google Scholar]
  93. 93. 
    Burr DB, Martin RB. 1993. Calculating the probability that microcracks initiate resorption spaces. J. Biomech. 26:613–16
    [Google Scholar]
  94. 94. 
    Burr DB, Martin RB, Schaffler MB, Radin EL 1985. Bone remodeling in response to in vivo fatigue microdamage. J. Biomech. 18:189–200
    [Google Scholar]
  95. 95. 
    Bentolila V, Boyce TM, Fyhrie DP, Drumb R, Skerry TM, Schaffler MB 1998. Intracortical remodeling in adult rat long bones after fatigue loading. Bone 23:275–81
    [Google Scholar]
  96. 96. 
    Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB 2009. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Miner. Res. 24:597–605
    [Google Scholar]
  97. 97. 
    Cheung WY, Fritton JC, Morgan SA, Seref-Ferlengez Z, Basta-Pljakic J et al. 2016. Pannexin-1 and P2X7-receptor are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes. J. Bone Miner. Res. 31:890–99
    [Google Scholar]
  98. 98. 
    Harris SE, MacDougall M, Horn D, Woodruff K, Zimmer SN et al. 2012. Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects. Bone 50:42–53
    [Google Scholar]
  99. 99. 
    Blanchard F, Duplomb L, Baud'huin M, Brounais B 2009. The dual role of IL-6-type cytokines on bone remodeling and bone tumors. Cytokine Growth Factor Rev 20:19–28
    [Google Scholar]
  100. 100. 
    Pathak JL, Bakker AD, Luyten FP, Verschueren P, Lems WF et al. 2016. Systemic inflammation affects human osteocyte-specific protein and cytokine expression. Calcif. Tissue Int. 98:596–608
    [Google Scholar]
  101. 101. 
    Kogianni G, Mann V, Noble BS 2008. Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J. Bone Miner. Res. 23:915–27
    [Google Scholar]
  102. 102. 
    He F, Bai J, Wang J, Zhai J, Tong L, Zhu G 2019. Irradiation-induced osteocyte damage promotes HMGB1-mediated osteoclastogenesis in vitro. J. Cell. Physiol. 234:17314–25
    [Google Scholar]
  103. 103. 
    Nakano M, Ikegame M, Igarashi-Migitaka J, Maruyama Y, Suzuki N, Hattori A 2019. Suppressive effect of melatonin on osteoclast function via osteocyte calcitonin. J. Endocrinol. 242:13–23
    [Google Scholar]
  104. 104. 
    O'Brien W, Fissel BM, Maeda Y, Yan J, Ge X et al. 2016. RANK-independent osteoclast formation and bone erosion in inflammatory arthritis. Arthritis Rheumatol 68:2889–900
    [Google Scholar]
  105. 105. 
    Parfitt AM. 1982. The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab. Bone Dis. Relat. Res. 4:1–6
    [Google Scholar]
  106. 106. 
    Ajubi NE, Klein-Nulend J, Nijweide PJ, Vrijheid-Lammers T, Alblas MJ, Burger EH 1996. Pulsating fluid flow increases prostaglandin production by cultured chicken osteocytes—a cytoskeleton-dependent process. Biochem. Biophys. Res. Commun. 225:62–68
    [Google Scholar]
  107. 107. 
    Joeng KS, Lee YC, Lim J, Chen Y, Jiang MM et al. 2017. Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J. Clin. Investig. 127:2678–88
    [Google Scholar]
  108. 108. 
    Kringelbach TM, Aslan D, Novak I, Ellegaard M, Syberg S et al. 2015. Fine-tuned ATP signals are acute mediators in osteocyte mechanotransduction. Cell Signal 27:2401–9
    [Google Scholar]
  109. 109. 
    van Bezooijen RL, Deruiter MC, Vilain N, Monteiro RM, Visser A et al. 2007. SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development. Dev. Dyn. 236:606–12
    [Google Scholar]
  110. 110. 
    Chan BY, Fuller ES, Russell AK, Smith SM, Smith MM et al. 2011. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage 19:874–85
    [Google Scholar]
  111. 111. 
    Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F et al. 2006. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–66
    [Google Scholar]
  112. 112. 
    Paic F, Igwe JC, Nori R, Kronenberg MS, Franceschetti T et al. 2009. Identification of differentially expressed genes between osteoblasts and osteocytes. Bone 45:682–92
    [Google Scholar]
  113. 113. 
    Taylor S, Ominsky MS, Hu R, Pacheco E, He YD et al. 2016. Time-dependent cellular and transcriptional changes in the osteoblast lineage associated with sclerostin antibody treatment in ovariectomized rats. Bone 84:148–59
    [Google Scholar]
  114. 114. 
    Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR et al. 2008. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283:5866–75
    [Google Scholar]
  115. 115. 
    Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q et al. 2005. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–83
    [Google Scholar]
  116. 116. 
    Genetos DC, Yellowley CE, Loots GG 2011. Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PLOS ONE 6:e17772
    [Google Scholar]
  117. 117. 
    Igwe JC, Jiang X, Paic F, Ma L, Adams DJ et al. 2009. Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J. Cell. Biochem. 108:621–30
    [Google Scholar]
  118. 118. 
    Feng JQ, Ward LM, Liu S, Lu Y, Xie Y et al. 2006. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38:1310–15
    [Google Scholar]
  119. 119. 
    Karsenty G. 2017. Update on the biology of osteocalcin. Endocr. Pract. 23:1270–74
    [Google Scholar]
  120. 120. 
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y et al. 2004. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Investig. 113:561–68
    [Google Scholar]
  121. 121. 
    Quarles LD. 2012. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat. Rev. Endocrinol. 8:276–86
    [Google Scholar]
  122. 122. 
    Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD 2003. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J. Biol. Chem. 278:37419–26
    [Google Scholar]
  123. 123. 
    Rowe PS. 2004. The wrickkened pathways of FGF23, MEPE and PHEX. Crit. Rev. Oral Biol. Med. 15:264–81
    [Google Scholar]
  124. 124. 
    Rowe PS, Garrett IR, Schwarz PM, Carnes DL, Lafer EM et al. 2005. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone 36:33–46
    [Google Scholar]
  125. 125. 
    Cheng B, Kato Y, Zhao S, Luo J, Sprague E et al. 2001. PGE2 is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. Endocrinology 142:3464–73
    [Google Scholar]
  126. 126. 
    Huang J, Romero-Suarez S, Lara N, Mo C, Kaja S et al. 2017. Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway. JBMR Plus 1:86–100
    [Google Scholar]
  127. 127. 
    Huang J, Wang K, Shiflett LA, Brotto L, Bonewald LF et al. 2019. Fibroblast Growth Factor 9 (FGF9)—a potential osteokine with dual effects: inhibition of myogenic differentiation, and enhancement of proliferation. Cell Cycle 18:356280
    [Google Scholar]
  128. 128. 
    Zoch ML, Clemens TL, Riddle RC 2016. New insights into the biology of osteocalcin. Bone 82:42–49
    [Google Scholar]
  129. 129. 
    Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y et al. 2018. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175:1756–68
    [Google Scholar]
  130. 130. 
    Kitase Y, Vallejo JA, Gutheil W, Vemula H, Jähn K et al. 2018. β-Aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep 22:1531–44
    [Google Scholar]
  131. 131. 
    Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C et al. 2015. The myokine irisin increases cortical bone mass. PNAS 112:12157–62
    [Google Scholar]
  132. 132. 
    Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L et al. 2017. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci. Rep. 7:2811
    [Google Scholar]
  133. 133. 
    Maurel DB, Jähn K, Lara-Castillo N 2017. Muscle-bone crosstalk: emerging opportunities for novel therapeutic approaches to treat musculoskeletal pathologies. Biomedicines 5:62
    [Google Scholar]
  134. 134. 
    Paszty C, Turn CH, Robinson MK 2010. Sclerostin: a gem from the genome leads to bone-building antibodies. J. Bone Miner. Res. 25:1897–904
    [Google Scholar]
  135. 135. 
    Ominsky MS, Boyce RW, Li X, Ke HZ 2017. Effects of sclerostin antibodies in animal models of osteoporosis. Bone 96:63–75
    [Google Scholar]
  136. 136. 
    McClung MR. 2018. Romosozumab for the treatment of osteoporosis. Osteoporos. Sarcopenia 4:11–15
    [Google Scholar]
  137. 137. 
    Imel E, White KE. 2018. Pharmacological management of X-linked hypophosphateaemia. Br. J. Clin. Pharmacol. 85:1188–98
    [Google Scholar]
  138. 138. 
    Bonewald LF, Wacker MJ. 2013. FGF23 production by osteocytes. Pediatr. Nephrol. 28:563–68
    [Google Scholar]
  139. 139. 
    Pereira RC, Jüppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K 2009. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45:1161–68
    [Google Scholar]
  140. 140. 
    Takeyari S, Yamamoto T, Kinoshita Y, Glorieux FH, Michigami T et al. 2014. Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome. Bone 67:56–62
    [Google Scholar]
  141. 141. 
    Leifheit-Nestler M, Haffner D. 2018. Paracrine effects of FGF23 on the heart. Front. Endocrinol. 9:278
    [Google Scholar]
  142. 142. 
    Zhao S, Kato Y, Zhang Y, Harris S, Ahuja SS, Bonewald LF 2002. MLO-Y4 osteocyte-like cells support osteoclast formation and activation. J. Bone Miner. Res. 17:2068–79
    [Google Scholar]
  143. 143. 
    Tanaka K, Yamaguchi Y, Hakeda Y 1995. Isolated chick osteocytes stimulate formation and bone‐resorbing activity of osteoclast‐like cells. J. Bone Miner. Metab. 13:61–70
    [Google Scholar]
  144. 144. 
    Miller PD. 2011. A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis. Ther. Adv. Musculoskel. Dis. 3:271–82
    [Google Scholar]
  145. 145. 
    Bellido T, Plotkin LI. 2011. Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 49:50–55
    [Google Scholar]
  146. 146. 
    Pajevic PD, Krause DS. 2019. Osteocyte regulation of bone and blood. Bone 119:13–18
    [Google Scholar]
  147. 147. 
    Atkinson EG, Delgado-Calle J. 2019. The emerging role of osteocytes in cancer in bone. JBMR Plus 3:e10186
    [Google Scholar]
  148. 148. 
    Zhou M, Li S, Pathak JL 2019. Pro-inflammatory cytokines and osteocytes. Curr. Osteoporos. Rep. 17:97–104
    [Google Scholar]
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