Сurrent concepts in physiological and reparative osteogenesis

Cover Page


Cite item

Full Text

Abstract

Studies conducted in the recent years by biologists strongly suggest that physiological and reparative osteogenesis, as well as of the functional, adaptive, and post-traumatic reconstruction of bone tissues are based on common and stereotypical molecular and cellular mechanisms. Our experimental studies have shown that all stages of the bone microstructure morphogenesis are synchronously and continuously associated with focal and stereotypical angiogenesis (capillarogenesis). A powerful factor in the implementation of reparative osteogenesis is the osteoinductive interaction of the ends of the damaged bone segments, which positively shows itself even in cases of large diastasis between the fragments (provided that the fragments are steadily fixed). After any kind of stable osteosynthesis, by ensuring the stability of the bone fragments for the entire period of consolidation, an endosteal cortical bone regeneration by direct osteogenesis (i.e. without fibro-cartilaginous tissue) is observed in the minimum amount at the shortest time period. Periosteal bone formation in this case is actually a reserve source of bone formation, which becomes effective during insufficiently stable conditions. The instability of the bone damage area particularly that of the metal implants results in the most severe destructive consequences. 

About the authors

G. A. Onoprienko

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: gao-1537@mail.ru

Onoprienko Gennadiy A. – MD, PhD, Professor, Corresponding Member of Russian Academy of Sciences, Professor of Chair of Traumatology and Orthopaedics, Postgraduate Training Faculty 

22–118 B. Gruzinskaya ul., Moscow, 123242

Россия

V. P. Voloshin

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Voloshin Viktor P. – MD, PhD, Professor; Head of Department of Traumatology and Orthopaedics, Head of Chair of Traumatology and Orthopaedics, Postgraduate Training Faculty

61/2 Shchepkina ul., Moscow, 129110

Россия

References

  1. Bonewald LF. Osteocytes: a proposed multifunctional bone cell. J Musculoskelet Neuronal Interact. 2002;2(3):239–41.
  2. Bonewald LF. Mechanosensation and Transduction in Osteocytes. Bonekey Osteovision. 2006;3(10):7–15. doi: 10.1138/20060233.
  3. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38. doi: 10.1002/jbmr.320.
  4. Turner CH, Pavalko FM. Mechanotransduction and functional response of the skeleton to physical stress: the mechanisms and mechanics of bone adaptation. J Orthop Sci. 1998;3(6): 346–55.
  5. Омельяненко НП, Слуцкий ЛИ. Соединительная ткань (гистофизиология и биохимия). В 2 т. Т. 1. М.: Известия; 2009. 380 с. Т. 2. М.: Известия; 2010. 599 с.
  6. Silver FH, Siperko LM. Mechanosensing and mechanochemical transduction: how is mechanical energy sensed and converted into chemical energy in an extracellular matrix? Crit Rev Biomed Eng. 2003;31(4):255–331.
  7. Yang W, Kalajzic I, Lu Y, Guo D, Harris MA, Gluhak-Heinrich J, Bonewald LF, Feng JQ, Rowe DW, Harris SE. In vitro and in vivo study on osteocyte-specific mechanical signaling pathways. J Musculoskelet Neuronal Interact. 2004;4(4):386–7.
  8. Liedert A, Kaspar D, Blakytny R, Claes L, Ignatius A. Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun. 2006;349(1):1–5. doi: 10.1016/j.bbrc.2006.07.214.
  9. Rubin J, Rubin C, Jacobs CR. Molecular pathways mediating mechanical signaling in bone. Gene. 2006;367:1–16. doi: 10.1016/j. gene.2005.10.028.
  10. Cowin SC. Mechanosensation and fluid transport in living bone. J Musculoskelet Neuronal Interact. 2002;2(3):256–60.
  11. Wang Y, McNamara LM, Schaffler MB, Weinbaum S. A model for the role of integrins in flow induced mechanotransduction in osteocytes. Proc Natl Acad Sci U S A. 2007;104(40): 15941–6. doi: 10.1073/pnas.0707246104.
  12. Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J Bone Miner Res. 2009;24(4):597–605. doi: 10.1359/ jbmr.081210.
  13. Huiskes R. If bone is the answer, then what is the question? J Anat. 2000;197(Pt 2):145–56. doi: 10.1046/j.1469-7580.2000.19720145.x.
  14. Taylor AF, Saunders MM, Shingle DL, Cimbala JM, Zhou Z, Donahue HJ. Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions. Am J Physiol Cell Physiol. 2007;292(1):C545–52. doi: 10.1152/ ajpcell.00611.2005.
  15. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23(3):279– 302. doi: 10.1210/edrv.23.3.0465.
  16. Spencer GJ, Hitchcock IS, Genever PG. Emerging neuroskeletal signalling pathways: a review. FEBS Lett. 2004;559(1–3):6–12. doi: 10.1016/S0014-5793(04)00053-5.
  17. Gu G, Mulari M, Peng Z, Hentunen TA, Väänänen HK. Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption. Biochem Biophys Res Commun. 2005;335(4):1095–101. doi: 10.1016/j.bbrc.2005.06.211.
  18. Fukumoto S, Martin TJ. Bone as an endocrine organ. Trends Endocrinol Metab. 2009;20(5): 230–6. doi: 10.1016/j.tem.2009.02.001.
  19. Mackie EJ. Osteoblasts: novel roles in orchestration of skeletal architecture. Int J Biochem Cell Biol. 2003;35(9):1301–5. doi: http://doi. org/10.1016/S1357-2725(03)00107-9.
  20. Miao D, He B, Jiang Y, Kobayashi T, Sorocéanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, Karaplis AC. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest. 2005;115(9): 2402–11. doi: 10.1172/JCI24918.
  21. Prêle CM, Horton MA, Caterina P, Stenbeck G. Identification of the molecular mechanisms contributing to polarized trafficking in osteoblasts. Exp Cell Res. 2003;282(1):24–34. doi: https://doi.org/10.1006/excr.2002.5668.
  22. Roberts WE, Morey ER. Proliferation and differentiation sequence of osteoblast histogenesis under physiological conditions in rat periodontal ligament. Am J Anat. 1985;174(2): 105–18. doi: 10.1002/aja.1001740202.
  23. Malluche HH, Faugere MC, Rush M, Friedler R. Osteoblastic insufficiency is responsible for maintenance of osteopenia after loss of ovarian function in experimental beagle dogs. Endocrinology. 1986;119(6):2649–54. doi: 10.1210/endo-119-6-2649.
  24. McCulloch CA, Heersche JN. Lifetime of the osteoblast in mouse periodontium. Anat Rec. 1988;222(2):128–35. doi: 10.1002/ ar.1092220204.
  25. Hock JM, Krishnan V, Onyia JE, Bidwell JP, Milas J, Stanislaus D. Osteoblast apoptosis and bone turnover. J Bone Miner Res. 2001;16(6): 975–84. doi: 10.1359/jbmr.2001.16.6.975.
  26. Frost HM. The biology of fracture healing. An overview for clinicians. Part I. Clin Orthop Relat Res. 1989;(248):283–93.
  27. Frost HM. Defining osteopenias and osteoporoses: another view (with insights from a new paradigm). Bone. 1997;20(5): 385–91. doi: https://doi.org/10.1016/S87563282(97)00019-7.
  28. Григорьев АИ, Воложин АИ, Ступаков ГП. Минеральный обмен у человека в условиях измененной гравитации. М.: Наука; 1994. 214 с.
  29. Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11(2):76–81. doi: 10.1016/j.molmed.2004.12.004.
  30. Case N, Ma M, Sen B, Xie Z, Gross TS, Rubin J. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J Biol Chem. 2008;283(43):29196–205. doi: 10.1074/jbc.M801907200.
  31. Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. 2009;458(7237):524–8. doi: 10.1038/nature07713.
  32. Ninomiya K, Miyamoto T, Imai J, Fujita N, Suzuki T, Iwasaki R, Yagi M, Watanabe S, Toyama Y, Suda T. Osteoclastic activity induces osteomodulin expression in osteoblasts. Biochem Biophys Res Commun. 2007;362(2):460–6. doi: 10.1016/j.bbrc.2007.07.193.
  33. Edwards CM, Mundy GR. Eph receptors and ephrin signaling pathways: a role in bone homeostasis. Int J Med Sci. 2008;5(5):263–72. doi: 10.7150/ijms.5.263.
  34. Irie N, Takada Y, Watanabe Y, Matsuzaki Y, Naruse C, Asano M, Iwakura Y, Suda T, Matsuo K. Bidirectional signaling through ephrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem. 2009;284(21):14637–44. doi: 10.1074/jbc.M807598200.
  35. Rosen CJ. Restoring aging bones. Sci Am. 2003;288(3):70–7.
  36. Noble BS, Reeve J. Osteocyte function, osteocyte death and bone fracture resistance. Mol Cell Endocrinol. 2000;159(1–2):7–13. doi:http://doi.org/10.1016/S0303-7207(99)00174-4.
  37. Teti A, Zallone A. Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone. 2009;44(1):11–6. doi: 10.1016/j.bone.2008.09.017.
  38. Аврунин АС. Остеоцитарное ремоделирование: история вопроса, современные представления и возможности клинической оценки. Травматология и ортопедия России. 2012;(1):128–34. doi:http://dx.doi.org/10.21823/2311-2905-2012--1-128-134.
  39. Оноприенко ГА, Волошин ВП. Микроциркуляция и регенерация костной ткани: теоретические и клинические аспекты. М.: Бином; 2017. 184 с.
  40. Simpson AH, Mills L, Noble B. The role of growth factors and related agents in accelerating fracture healing. J Bone Joint Surg Br. 2006;88(6): 701–5. doi: 10.1302/0301-620X.88B6.17524.
  41. Kaunitz JD, Yamaguchi DT. TNAP, TrAP, ecto-purinergic signaling, and bone remodeling. J Cell Biochem. 2008;105(3):655–62. doi: 10.1002/jcb.21885.
  42. Sims NA, Gooi JH. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol. 2008;19(5):444–51. doi: 10.1016/j.semcdb.2008.07.016.
  43. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7. doi: 10.1126/ science.275.5302.964.
  44. Koutroumpi M, Dimopoulos S, Psarra K, Kyprianou T, Nanas S. Circulating endothelial and progenitor cells: Evidence from acute and long-term exercise effects. World J Cardiol. 2012;4(12):312–26. doi: 10.4330/wjc.v4.i12.312.
  45. Kiefer F, Siekmann AF. The role of chemokines and their receptors in angiogenesis. Cell Mol Life Sci. 2011;68(17):2811–30. doi: 10.1007/ s00018-011-0677-7.
  46. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3): 399–408. doi: 10.1016/j.cell.2012.01.021.
  47. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71. doi: 10.1146/ annurev-pathol-012513-104720.
  48. Tsutsumi Y, Losordo DW. Double face of VEGF. Circulation. 2005;112(9):1248–50. doi: 10.1161/CIRCULATIONAHA.105.566166.
  49. Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 2006;9(4):225– 30. doi: 10.1007/s10456-006-9055-8.
  50. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med (Berl). 2009;87(6):549–60. doi: 10.1007/s00109-009-0458-z.
  51. Navarro-Sobrino M, Rosell A, Hernandez-Guillamon M, Penalba A, Ribó M, Alvarez-Sabín J, Montaner J. Mobilization, endothelial differentiation and functional capacity of endothelial progenitor cells after ischemic stroke. Microvasc Res. 2010;80(3):317–23. doi: 10.1016/j.mvr.2010.05.008.
  52. Dai J, Rabie AB. VEGF: an essential mediator of both angiogenesis and endochondral ossification. J Dent Res. 2007;86(10):937–50. doi: 10.1177/154405910708601006.
  53. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6): 669–76. doi: 10.1038/nm0603-669.
  54. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med (Berl). 1999;77(7):527–43.
  55. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. Circulation. 2004;109(21):2487–91. doi: 10.1161/01.CIR.0000128595.79378.FA.
  56. Mac Gabhann F, Popel AS. Systems biology of vascular endothelial growth factors. Microcirculation. 2008;15(8):715–38. doi: 10.1080/10739680802095964.
  57. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438(7070):937–45. doi: 10.1038/nature04479.
  58. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–71. doi: 10.1038/nrm1911.
  59. Isner JM, Kalka C, Kawamoto A, Asahara T. Bone marrow as a source of endothelial cells for natural and iatrogenic vascular repair. Ann N Y Acad Sci. 2001;953:75–84. doi: 10.1111/j.1749-6632.2001.tb02075.x.
  60. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84. doi: 10.1002/jcb.20886.
  61. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(Pt 11):2204–13. doi: 10.1242/jcs.02932.
  62. Fan L, Li J, Yu Z, Dang X, Wang K. The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. Biomed Res Int. 2014;2014:239356. doi: 10.1155/2014/239356.
  63. Yang YQ, Tan YY, Wong R, Wenden A, Zhang LK, Rabie AB. The role of vascular endothelial growth factor in ossification. Int J Oral Sci. 2012;4(2):64–8. doi: 10.1038/ijos.2012.33.
  64. Chen G, Deng C, Li YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 2012;8(2):272–88. doi: 10.7150/ijbs.2929.
  65. McMahon MS. Bone morphogenic protein 3 signaling in the regulation of osteogenesis. Orthopedics. 2012;35(11):920. doi: 10.3928/01477447-20121023-02.
  66. Berendsen AD, Olsen BR. How vascular endothelial growth factor-A (VEGF) regulates differentiation of mesenchymal stem cells. J Histochem Cytochem. 2014;62(2):103–8. doi: 10.1369/0022155413516347.
  67. Ryoo HM, Lee MH, Kim YJ. Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene. 2006;366(1):51–7. doi: 10.1016/j.gene.2005.10.011.
  68. Friedman MS, Long MW, Hankenson KD. Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. J Cell Biochem. 2006;98(3): 538–54. doi: 10.1002/jcb.20719.
  69. Akiyama I, Yoshino O, Osuga Y, Shi J, Harada M, Koga K, Hirota Y, Hirata T, Fujii T, Saito S, Kozuma S. Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells. Reprod Sci. 2014;21(4):477–82. doi: 10.1177/1933719113503411.
  70. Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE. Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop Relat Res. 2002;(395):110–20.
  71. Einhorn TA. Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am. 2003;85-A Suppl 3:82–8.
  72. Булатов АА, Савельев ВИ, Калинин АВ. Применение костных морфогенетических белков в эксперименте и клинике. Травматология и ортопедия России. 2005;(1):46–54.
  73. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511. doi: 10.1038/nri1391.
  74. Beutler B. Innate immunity: an overview. Mol Immunol. 2004;40(12):845–59. doi:http://doi.org/10.1016/j.molimm.2003.10.005.
  75. Zhu AJ, Scott MP. Incredible journey: how do developmental signals travel through tissue? Genes Dev. 2004;18(24):2985–97. doi: 10.1101/ gad.1233104.
  76. Ozaki K, Leonard WJ. Cytokine and cytokine receptor pleiotropy and redundancy. J Biol Chem. 2002;277(33):29355–8. doi: 10.1074/jbc.R200003200.
  77. Лаврищева ГИ, Оноприенко ГА. Морфологические и клинические аспекты репаративной регенерации опорных органов и тканей. М.: Медицина; 1996. 208 с.
  78. Оноприенко ГА. Микроциркуляция и регенерация костной ткани. В: Сборник тезисов IX съезда травматологов-ортопедов России. Саратов, 15–17 сентября 2010 г. Саратов; 2010. Т. 3. с. 1128–9.
  79. Оноприенко ГА. Васкуляризация костей при переломах и дефектах. М.: Медицина; 1995. 222 с.
  80. Kasperk CH, Börcsök I, Schairer HU, Schneider U, Nawroth PP, Niethard FU, Ziegler R. Endothelin-1 is a potent regulator of human bone cell metabolism in vitro. Calcif Tissue Int. 1997;60(4):368–74.
  81. Nakagawa M, Kaneda T, Arakawa T, Morita S, Sato T, Yomada T, Hanada K, Kumegawa M, Hakeda Y. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett. 2000;473(2):161–4. doi: 10.1016/S0014-5793(00)01520-9.
  82. Street J, Bao M, deGuzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99(15): 9656–61. doi: 10.1073/pnas.152324099.
  83. Gori F, Schipani E, Demay MB. Fibromodulin is expressed by both chondrocytes and osteoblasts during fetal bone development. J Cell Biochem. 2001;82(1):46–57.
  84. Шевцов ВИ, Дьячков АН, Мигалкин НС, Ручкина ИВ, Осипова ЕВ. Изучение процесса остеогенеза в циркулярных дефектах длинных костей (экспериментальное исследование). Бюллетень Восточно-Сибирского научного центра Сибирского отделения Российской академии медицинских наук. 2007;(6):163–8.
  85. Poplich LS, Salkeld SL, Rueger DC. Critical and noncritical size defect healing with osteogenic protein. Trans Orthop Res Soc. 1997;22:600.
  86. Chen X, Kidder LS, Lew WD. Osteogenic protein-1 induced bone formation in an infected segmental defect in the rat femur. J Orthop Res. 2002;20(1):142–50. doi: 10.1016/S0736-0266(01)00060

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2017 Onoprienko G.A., Voloshin V.P.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies