Osteocytes and Bone Regeneration

  • Gerald J. Atkins
  • Matthew Prideaux
  • David M. FindlayEmail author
Part of the Mechanical Engineering Series book series (MES)


Bone integrity is essential to maintain its load-bearing capacity and to resist fractures. However, the skeleton can be subject to multiple insults during life, from subtle matrix damage in otherwise intact bone, to frank fracture. Fortunately, bone has a remarkable capacity to repair but because this does not always occur spontaneously, particularly in older individuals, a greater knowledge of the mechanisms of repair is required to enable intelligent intervention. To date, a great deal has been learnt about the roles of osteoblasts and osteoclasts in bone repair, while potential roles of the matrix embedded osteocytes has been much less investigated. Here, we review the evidence for osteocyte involvement in the repair of defects within the bone matrix, such as matrix microdamage, and their potential role in maintenance of a healthy and strong matrix by remodelling the bone from within. We also speculate as to whether osteocytes might be involved in the repair of macro-fractures, by serving as progenitors for the cells that contribute to fracture repair.


Bone Matrix Bone Repair Osteocyte Apoptosis SOST Gene Sclerostin Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Funding from the National Health and Medical Research Council of Australia and the support of the Department of Orthopaedics and Trauma, Royal Adelaide Hospital and the University of Adelaide, Adelaide, Australia is gratefully acknowledged.


  1. Addison WN, Masica DL, Gray JJ, McKee MD (2010) Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 25(4):695–705. doi: 10.1359/jbmr.090832 Google Scholar
  2. Al-Dujaili SA, Lau E, Al-Dujaili H, Tsang K, Guenther A, You L (2011) Apoptotic osteocytes regulate osteoclast precursor recruitment and differentiation in vitro. J Cell Biochem 112(9):2412–2423. doi: 10.1002/jcb.23164 CrossRefGoogle Scholar
  3. Atkins GJ, Findlay DM (2012) Osteocyte regulation of bone mineral: a little give and take. Osteoporos Int (a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA) 23(8):2067–2079. doi: 10.1007/s00198-012-1915-z CrossRefGoogle Scholar
  4. Atkins GJ, Welldon KJ, Holding CA, Haynes DR, Howie DW, Findlay DM (2009) The induction of a catabolic phenotype in human primary osteoblasts and osteocytes by polyethylene particles. Biomaterials 30(22):3672–3681. doi: 10.1016/j.biomaterials.2009.03.035 CrossRefGoogle Scholar
  5. Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/Preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 26(7):1425–1436. doi: 10.1002/jbmr.345 CrossRefGoogle Scholar
  6. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19(2):179–192. doi: 10.1038/nm.3074 nm.3074 [pii]
  7. Belanger LF, Belanger C, Semba T (1967) Technical approaches leading to the concept of osteocytic osteolysis. Clin Orthop Relat Res 54:187–196Google Scholar
  8. Boabaid F, Cerri PS, Katchburian E (2001) Apoptotic bone cells may be engulfed by osteoclasts during alveolar bone resorption in young rats. Tissue Cell 33 (4):318-325. doi: 10.1054/tice.2001.0179 S0040-8166(01)90179-X [pii]
  9. Boland K, Flanagan L, Prehn JH (2013) Paracrine control of tissue regeneration and cell proliferation by Caspase-3. Cell Death Dis 4:e725. doi: 10.1038/cddis.2013.250 cddis2013250 [pii]
  10. Bonewald LF (2007) Osteocytes as dynamic, multifunctional cells. Ann NY Acad Sci 1116:281–290CrossRefGoogle Scholar
  11. Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42(4):606–615CrossRefGoogle Scholar
  12. Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U, Cogger VC, Svistounov D, Zhang Y, Cooney GJ, Buttgereit F, Dunstan CR, Gundberg C, Zhou H, Seibel MJ (2012) Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest 122(11):4172–4189. doi: 10.1172/JCI63377 63377 [pii]
  13. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68(3):577–589CrossRefGoogle Scholar
  14. 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 Min Res (the official journal of the American Society for Bone and Mineral Research) 24(4):597–605. doi: 10.1359/jbmr.081210 CrossRefGoogle Scholar
  15. Cheung WY, Liu C, Tonelli-Zasarsky RM, Simmons CA, You L (2011) Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. J Orthop Res (official publication of the Orthopaedic Research Society) 29(4):523–530. doi: 10.1002/jor.21283 CrossRefGoogle Scholar
  16. Colnot C (2009) Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res 24(2):274–282. doi: 10.1359/jbmr.081003 CrossRefGoogle Scholar
  17. Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell … and more. Endocr Rev 34 (5):658–690. doi: 10.1210/er.2012-1026 er.2012-1026 [pii]
  18. Dunstan CR, Somers NM, Evans RA (1993) Osteocyte death and hip fracture. Calcif Tissue Int 53(1):S113–S116; discussion S116–S117Google Scholar
  19. Elmardi AS, Katchburian MV, Katchburian E (1990) Electron microscopy of developing calvaria reveals images that suggest that osteoclasts engulf and destroy osteocytes during bone resorption. Calcif Tissue Int 46(4):239–245CrossRefGoogle Scholar
  20. Eser P, Frotzler A, Zehnder Y, Wick L, Knecht H, Denoth J, Schiessl H (2004) Relationship between the duration of paralysis and bone structure: a pQCT study of spinal cord injured individuals. Bone 34(5):869–880. doi: 10.1016/j.bone.2004.01.001 S8756328204000146 [pii]
  21. Findlay DM, Atkins GJ (2011) Relationship between serum RANKL and RANKL in bone. Osteoporos Int (a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA) 22(10):2597–2602. doi: 10.1007/s00198-011-1740-9 CrossRefGoogle Scholar
  22. Fritton SP, Weinbaum S (2009) Fluid and solute transport in bone: flow-induced mechanotransduction. Ann Rev Fluid Mech 41:347–374CrossRefGoogle Scholar
  23. Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, Lotinun S, Baron R, Bonewald L, Feng JQ, Chen M, Weinstein LS, Wu JY, Kronenberg HM, Scadden DT, Divieti Pajevic P (2013) Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood 121 (6):930–939. doi: 10.1182/blood-2012-06-437160 blood-2012-06-437160 [pii]
  24. Gamie Z, Korres N, Leonidou A, Gray AC, Tsiridis E (2012) Sclerostin monoclonal antibodies on bone metabolism and fracture healing. Expert Opin Investig Drugs 21(10):1523–1534. doi: 10.1517/13543784.2012.713936 CrossRefGoogle Scholar
  25. Han Y, Cowin SC, Schaffler MB, Weinbaum S (2004) Mechanotransduction and strain amplification in osteocyte cell processes. Proc Natl Acad Sci USA 101(47):16689–16694CrossRefGoogle Scholar
  26. Herman BC, Cardoso L, Majeska RJ, Jepsen KJ, Schaffler MB (2010) Activation of bone remodeling after fatigue: differential response to linear microcracks and diffuse damage. Bone 47 (4):766–772. doi: 10.1016/j.bone.2010.07.006 S8756–3282(10)01349-9 [pii]
  27. Ito N, Findlay DM, Atkins GJ (2014) Osteocyte communication with the kidney via the production of FGF23: remote control of phosphate homeostasis. Clin Rev Bone Min Metab 12(1):44–58. doi: 10.1007/s12018-014-9155-8
  28. Jones SJ, Boyde A (1977) Some morphological observations on osteoclasts. Cell Tissue Res 185(3):387–397CrossRefGoogle Scholar
  29. Kennedy OD, Herman BC, Laudier DM, Majeska RJ, Sun HB, Schaffler MB (2012) Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 50 (5):1115–1122. doi: 10.1016/j.bone.2012.01.025 S8756-3282(12)00053-1 [pii]
  30. Kogawa M, Wijenayaka AR, Ormsby RT, Thomas GP, Anderson PH, Bonewald LF, Findlay DM, Atkins GJ (2013) Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Mineral Research (the official journal of the American Society for Bone and Mineral Research) 28(12):2436–2448. doi: 10.1002/jbmr.2003 CrossRefGoogle Scholar
  31. Kogianni G, Mann V, Noble BS (2008) Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 23(6):915–927CrossRefGoogle Scholar
  32. Kurata K, Heino TJ, Higaki H, Vaananen HK (2006) Bone marrow cell differentiation induced by mechanically damaged osteocytes in 3D gel-embedded culture. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 21(4):616–625CrossRefGoogle Scholar
  33. Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A (2004) Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res 19(6):1006–1012. doi: 10.1359/JBMR.040307 CrossRefGoogle Scholar
  34. Li C, Ominsky MS, Tan HL, Barrero M, Niu QT, Asuncion FJ, Lee E, Liu M, Simonet WS, Paszty C, Ke HZ (2011) Increased callus mass and enhanced strength during fracture healing in mice lacking the sclerostin gene. Bone 49(6):1178–1185. doi: 10.1016/j.bone.2011.08.012 S8756-3282(11)01155-0 [pii]
  35. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 24(10):1651–1661. doi: 10.1359/jbmr.090411 CrossRefGoogle Scholar
  36. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70(1):11–19CrossRefGoogle Scholar
  37. McBride SH, Silva MJ (2012) Adaptive and injury response of bone to mechanical loading. Bonekey Osteovision 1. doi: 10.1038/bonekey.2012.192 192 [pii]
  38. Mori S, Burr DB (1993) Increased intracortical remodeling following fatigue damage. Bone 14(2):103–109CrossRefGoogle Scholar
  39. Moustafa A, Sugiyama T, Prasad J, Zaman G, Gross TS, Lanyon LE, Price JS (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225–1234. doi: 10.1007/s00198-011-1656-4  
  40. Murao H, Yamamoto K, Matsuda S, Akiyama H (2013) Periosteal cells are a major source of soft callus in bone fracture. J Bone Miner Metab 31(4):390–398. doi: 10.1007/s00774-013-0429-x CrossRefGoogle Scholar
  41. Nakano Y, Toyosawa S, Takano Y (2004) Eccentric localization of osteocytes expressing enzymatic activities, protein, and mRNA signals for type 5 tartrate-resistant acid phosphatase (TRAP). J Histochem Cytochem 52(11):1475–1482CrossRefGoogle Scholar
  42. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature medicine 17 (10):1231–1234. doi: 10.1038/nm.2452 nm.2452 [pii]
  43. Noble BS, Peet N, Stevens HY, Brabbs A, Mosley JR, Reilly GC, Reeve J, Skerry TM, Lanyon LE (2003) Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Physiol Cell Physiol 284(4):934–943CrossRefGoogle Scholar
  44. Ominsky MS, Li C, Li X, Tan HL, Lee E, Barrero M, Asuncion FJ, Dwyer D, Han CY, Vlasseros F, Samadfam R, Jolette J, Smith SY, Stolina M, Lacey DL, Simonet WS, Paszty C, Li G, Ke HZ (2011) Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J Bone Miner Res 26(5):1012–1021. doi: 10.1002/jbmr.307 CrossRefGoogle Scholar
  45. Parfitt AM (1998) Osteoclast precursors as leukocytes: importance of the area code. Bone 23(6):491–494CrossRefGoogle Scholar
  46. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. Faseb J 19(13):1842–1844Google Scholar
  47. Prasadam I, Zhou Y, Du Z, Chen J, Crawford R, Xiao Y (2014) Osteocyte-induced angiogenesis via VEGF-MAPK-dependent pathways in endothelial cells. Mol Cell Biochem 386(1–2):15–25. doi: 10.1007/s11010-013-1840-2 CrossRefGoogle Scholar
  48. Price C, Zhou X, Li W, Wang L (2011) Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: direct evidence for load-induced fluid flow. J Bone Min Res 26(2):277–285. doi: 10.1002/jbmr.211
  49. Qing H, Bonewald L (2009) Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int J Oral Sci 1(2):59–65CrossRefGoogle Scholar
  50. Qing H, Ardeshipour L, Divieti Pajevic D, Dusevich V, Jahn K, Kato S, Wysolmerski J, Bonewald L (2012) Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bon Min Res 27(5):1018–1029. doi: 10.1002/jbmr.1567[doi] CrossRefGoogle Scholar
  51. Qiu S, Rao DS, Palnitkar S, Parfitt AM (2003) Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 18(9):1657–1663CrossRefGoogle Scholar
  52. Robey PG, Termine JD (1985) Human bone cells in vitro. Calcif Tissue Int 37(5):453–460CrossRefGoogle Scholar
  53. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/sclerostin. J Biol Chem 283(9):5866–5875CrossRefGoogle Scholar
  54. Rowe PS (2012) Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Exp 22 (1):61-86 7b6c4b2a01f0c06f,621a8a161e01f522 [pii]Google Scholar
  55. Santos A, Bakker AD, Klein-Nulend J (2009) The role of osteocytes in bone mechanotransduction. Osteoporos Int (a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA) 20(6):1027–1031. doi: 10.1007/s00198-009-0858-5 CrossRefGoogle Scholar
  56. Stevens J, Ray RD (1967) An experimental comparison of living and dead bone in rats. 3. Uptake of radioactive isotopes. J Bone Joint Surg Br 49(1):154–163Google Scholar
  57. Suzuki R, Domon T, Wakita M, Akisaka T (2003) The reaction of osteoclasts when releasing osteocytes from osteocytic lacunae in the bone during bone modeling. Tissue Cell 35 (3):189–197. S004081660300020X [pii]Google Scholar
  58. Tang SY, Herber RP, Ho SP, Alliston T (2012) Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 27(9):1936–1950. doi: 10.1002/jbmr.1646 CrossRefGoogle Scholar
  59. Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K (2007) Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 5(6):464–475CrossRefGoogle Scholar
  60. Tazawa K, Hoshi K, Kawamoto S, Tanaka M, Ejiri S, Ozawa H (2004) Osteocytic osteolysis observed in rats to which parathyroid hormone was continuously administered. J Bone Miner Metab 22(6):524–529. doi: 10.1007/s00774-004-0519-x CrossRefGoogle Scholar
  61. Teti A, Zallone A (2009) Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 44(1):11–16CrossRefGoogle Scholar
  62. Torreggiani E, Matthews BG, Pejda S, Matic I, Horowitz MC, Grcevic D, Kalajzic I (2013) Preosteocytes/osteocytes have the potential to dedifferentiate becoming a source of osteoblasts. PLoS One 8 (9):e75204. doi: 10.1371/journal.pone.0075204 PONE-D-13-16597 [pii]
  63. Ushiku C, Adams DJ, Jiang X, Wang L, Rowe DW (2010) Long bone fracture repair in mice harboring GFP reporters for cells within the osteoblastic lineage. J Orthop Res 28(10):1338–1347. doi: 10.1002/jor.21105 CrossRefGoogle Scholar
  64. Verborgt O, Tatton NA, Majeska RJ, Schaffler MB (2002) Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation? J Bone Min Res (the official journal of the American Society for Bone and Mineral Research) 17(5):907–914. doi: 10.1359/jbmr.2002.17.5.907 CrossRefGoogle Scholar
  65. Welldon KJ, Findlay DM, Evdokiou A, Ormsby RT, Atkins GJ (2013) Calcium induces pro-anabolic effects on human primary osteoblasts associated with acquisition of mature osteocyte markers. Mol Cell Endocrinol 376 (1–2):85–92. doi: 10.1016/j.mce.2013.06.013 S0303-7207(13)00251-7 [pii]
  66. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ (2011) Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PloS one 6 (10):e25900. doi: 10.1371/journal.pone.0025900 PONE-D-11-07621 [pii]
  67. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17(10):1235–1241. doi: 10.1038/nm.2448 nm.2448 [pii]
  68. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95(7):3597–3602CrossRefGoogle Scholar
  69. Zhu H, Guo ZK, Jiang XX, Li H, Wang XY, Yao HY, Zhang Y, Mao N (2010) A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat Protoc 5 (3):550–560. doi: 10.1038/nprot.2009.238 nprot.2009.238 [pii]
  70. Zimmerman MA, Huang Q, Li F, Liu X, Li CY (2013) Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy. Semin Radiat Oncol 23 (4):288–295. doi: 10.1016/j.semradonc.2013.05.003 S1053-4296(13)00044-1 [pii]

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Gerald J. Atkins
    • 1
  • Matthew Prideaux
    • 1
  • David M. Findlay
    • 1
    Email author
  1. 1.Bone Cell Biology Group, Centre for Orthopaedic and Trauma ResearchThe University of AdelaideAdelaideAustralia

Personalised recommendations