Physiological role of growth factors and bone morphogenetic proteins in osteogenesis and bone fracture healing: а review

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Abstract

The repair of large bone defects remains a major clinical orthopedic challenge. Bone regeneration and fracture healing is a complex physiological mechanisms regulated by a large number of biologically active molecules. Multiple factors regulate this cascade of molecular events, which affects different stages in the osteoblast and chondroblast lineage during such processes as migration, proliferation, chemotaxis, differentiation, inhibition, and extracellular protein synthesis. A recent review has focused on the mechanisms by which growth and differentiation factors regulate the fracture healing process. Rapid progress in skeletal cellular and molecular biology has led to identification of many signaling molecules associated with formation of skeletal tissues, including a large family of growth factors (transforming growth factor-β and bone morphogenetic proteins, fibroblast growth factor, insulin-like growth factor, vascular endothelial growth factor, platelet-derived growth factor, cytokines and interleukins). There is increasing evidence indicating that they are critical regulators of cellular proliferation, differentiation, extracellular matrix biosynthesis and bone mineralization. A clear understanding of cellular and molecular pathways involved in fracture healing is not only critical for improvement of fracture treatments, but it may also enhance further our knowledge of mechanisms involved in skeletal growth and repair, as well as mechanisms of aging. This suggests that, in the future, they may play a major role in the treatment of bone disease and fracture repair.

About the authors

S. Sagalovsky

Median Clinic

Author for correspondence.
Email: s.sagalovsky@gmail.com

MD, PhD, Department of Orthopedics

Russian Federation

References

  1. Bais M, McLean J, Sebastiani P, Young M, Wigner N, Smith T, Kotton DN, Einhorn TA, Gerstenfeld LC. Transcriptional analysis of fracture healing and the induction of embryonic stem cell-related genes. PLoS One. 2009;4(5):e5393.
  2. Kwong FN, Harris MB. Recent developments in the biology of fracture repair. J Am Acad Orthop Surg. 2008;16(11):619–25.
  3. Tosounidis T, Kontakis G, Nikolaou V, Papathanassopoulos A, Giannoudis PV. Fracture healing and bone repair: an update. Trauma. 2009;11(3):145–56.
  4. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133–43.
  5. Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551–5. 6. Yamagiwa H, Endo N. Bone fracture and the healing mechanisms. Histological aspect of fracture healing. Primary and secondary healing. Clin Calcium. 2009;19(5):627–33.
  6. Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: which are the important molecules? Injury. 2007;38 Suppl 1:S11–25.
  7. Bastian O, Pillay J, Alblas J, Leenen L, Koenderman L, Blokhuis T. Systemic inflammation and fracture healing. J Leukoc Biol. 2011;89(5): 669–73.
  8. Balga R, Wetterwald A, Portenier J, Dolder S, Mueller C, Hofstetter W. Tumor necrosis factor-alpha: alternative role as an inhibitor of osteoclast formation in vitro. Bone. 2006;39(2):325–35.
  9. Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko Camacho N, Bostrom MP. Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone. 2007;41(6):928–36.
  10. Granero-Molto F, Weis JA, Miga MI, Landis B, Myers TJ, O'Rear L, Longobardi L, Jansen ED, Mortlock DP, Spagnoli A. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. 2009;27(8): 1887–98.
  11. Bais MV, Wigner N, Young M, Toholka R, Graves DT, Morgan EF, Gerstenfeld LC, Einhorn TA. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells. Bone. 2009;45(2):254–66.
  12. Kolar P, Schmidt-Bleek K, Schell H, Gaber T, Toben D, Schmidmaier G, Perka C, Buttgereit F, Duda GN. The early fracture hematoma and its potential role in fracture healing. Tissue Eng Part B Rev. 2010;16(4):427–34.
  13. Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005;36(12):1392–404.
  14. Gerstenfeld LC, Alkhiary YM, Krall EA, Nicholls FH, Stapleton SN, Fitch JL, Bauer M, Kayal R, Graves DT, Jepsen KJ, Einhorn TA. Three-dimensional reconstruction of fracture callus morphogenesis. J Histochem Cytochem. 2006;54(11):1215–28.
  15. Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV. Fracture vascularity and bone healing: a systematic review of the role of VEGF. Injury. 2008;39 Suppl 2: S45–57.
  16. Arvidson K, Abdallah BM, Applegate LA, Baldini N, Cenni E, Gomez-Barrena E, Granchi D, Kassem M, Konttinen YT, Mustafa K, Pioletti DP, Sillat T, Finne-Wistrand A. Bone regeneration and stem cells. J Cell Mol Med. 2011;15(4):718–46.
  17. Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor-beta1 to the bone. Endocr Rev. 2005;26(6):743–74.
  18. Myers TJ, Yan Y, Granero-Molto F, Weis JA, Longobardi L, Li T, Li Y, Contaldo C, Ozkan H, Spagnoli A. Systemically delivered insulin-like growth factor-I enhances mesenchymal stem cell-dependent fracture healing. Growth Factors. 2012;30(4):230–41.
  19. Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res. 2008;87(2):107–18.
  20. Marie PJ, Miraoui H, Severe N. FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors. 2012;30(2):117–23.
  21. Fei Y, Gronowicz G, Hurley MM. Fibroblast growth factor-2, bone homeostasis and fracture repair. Curr Pharm Des. 2013;19(19): 3354–63.
  22. Coutu DL, Galipeau J. Roles of FGF signaling in stem cell self-renewal, senescence and aging. Aging (Albany NY). 2011;3(10):920–33.
  23. Du X, Xie Y, Xian CJ, Chen L. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol. 2012;227(12):3731–43.
  24. Schmid GJ, Kobayashi C, Sandell LJ, Ornitz DM. Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn. 2009;238(3):766–74.
  25. Nakajima F, Nakajima A, Ogasawara A, Moriya H, Yamazaki M. Effects of a single percutaneous injection of basic fibroblast growth factor on the healing of a closed femoral shaftfracture in the rat. Calcif Tissue Int. 2007;81(2): 132–8.
  26. Marie PJ. Fibroblast growth factor signaling controlling bone formation: an update. Gene.2012;498(1):1–4.
  27. Su N, Du X, Chen L. FGF signaling: its role in bone development and human skeleton diseases. Front Biosci. 2008;13:2842–65.
  28. Kawaguchi H. Bone fracture and the healing mechanisms. Fibroblast growth factor-2 and fracture healing. Clin Calcium. 2009;19(5): 653–9.
  29. Kidder LS, Chen X, Schmidt AH, Lew WD. Osteogenic protein-1 overcomes inhibition of fracture healing in the diabetic rat: a pilot study. Clin Orthop Relat Res. 2009;467(12): 3249–56.
  30. Kempen DH, Creemers LB, Alblas J, Lu L, Verbout AJ, Yaszemski MJ, Dhert WJ. Growth factor interactions in bone regeneration. Tissue Eng Part B Rev. 2010;16(6):551–66.
  31. Reumann MK, Nair T, Strachna O, Boskey AL, Mayer-Kuckuk P. Production of VEGF receptor 1 and 2 mRNA and protein during endochondral bone repair is differential and healing phase specific. J Appl Physiol (1985). 2010;109(6):1930–8.
  32. Jacobsen KA, Al-Aql ZS, Wan C, Fitch JL, Stapleton SN, Mason ZD, Cole RM, Gilbert SR, Clemens TL, Morgan EF, Einhorn TA, Gerstenfeld LC. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J Bone Miner Res. 2008;23(5):596–609.
  33. Beamer B, Hettrich C, Lane J. Vascular endothelial growth factor: an essential component of angiogenesis and fracture healing. HSS J. 2010;6(1):85–94.
  34. Maes C, Carmelit G. Vascular and nonvascular roles of VEGF in bone development. In: Ruhrberg C, editor. VEGF in Development. Austin, Texas: Landes Bioscience; 2008. p. 79–90.
  35. Dai J, Rabie AB. VEGF: an essential mediator of both angiogenesis and endochondral ossification. J Dent Res. 2007;86(10):937–50.
  36. Wang CJ, Huang KE, Sun YC, Yang YJ, Ko JY, Weng LH, Wang FS. VEGF modulates angiogenesis and osteogenesis in shockwave-promoted fracture healing in rabbits. J Surg Res. 2011;171(1):114–9.
  37. Ogilvie CM, Lu C, Marcucio R, Lee M, Thompson Z, Hu D, Helms JA, Miclau T. Vascular endothelial growth factor improves bone repair in a murine nonunion model. Iowa Orthop J. 2012;32:90–4.
  38. 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.
  39. Roy H, Bhardwaj S, Yla-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580(12):2879–87.
  40. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22(10):1276–312.
  41. Bordei P. Locally applied platelet-derived growth factor accelerates fracture healing. J Bone Joint Surg Br. 2011;93(12):1653–9.
  42. Donovan J, Shiwen X, Norman J, Abraham D. Platelet-derived growth factor alpha and beta receptors have overlapping functional activities towards fibroblasts. Fibrogenesis Tissue Repair. 2013;6(1):10.
  43. Siwicka KA, Kitoh H, Kawasumi M, Ishiguro N. Spatial and temporal distribution of growth factors receptors in the callus: implications for improvement of distraction osteogenesis. Nagoya J Med Sci. 2011;73(3–4):117–27.
  44. Makhdom AM, Hamdy RC. The role of growth factors on acceleration of bone regeneration during distraction osteogenesis. Tissue Eng Part B Rev. 2013;19(5):442–53.
  45. Santibanez JF, Quintanilla M, Bernabeu C. TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011;121(6):233–51.
  46. Huang F, Chen YG. Regulation of TGF-. receptor activity. Cell Biosci. 2012;2:9.
  47. Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.
  48. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9 Suppl 1:S1.
  49. Sagalovsky S. Bone remodeling: cellular-molecular biology and role cytokine RANK-RANKL-osteoprotegerin (OPG) system and growth factors. Сrimea J Exptl Clin Med. 2013; 3(1–2):36–44.
  50. Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006;12(1):17–25.
  51. Karst M, Gorny G, Galvin RJ, Oursler MJ. Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation. J Cell Physiol. 2004;200(1):99–106.
  52. Nishimura R. A novel role for TGF-. in bone remodeling . IBMS Bone Key. 2009;6:434–8.
  53. Sarahrudi K, Thomas A, Mousavi M, Kaiser G, Kottstorfer J, Kecht M, Hajdu S, Aharinejad S. Elevated transforming growth factor-beta 1 (TGF-β1) levels in human fracture healing. Injury. 2011;42(8):833–7.
  54. 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.
  55. 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.
  56. Gazzerro E, Canalis E. Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord. 2006;7(1–2):51–65.
  57. Kugimiya F, Ohba S, Nakamura K, Kawaguchi H, Chung UI. Physiological role of bone morphogenetic proteins in osteogenesis. J Bone Miner Metab. 2006;24(2):95–9.
  58. Marsell R, Einhorn TA. The role of endogenous bone morphogenetic proteins in normal skeletal repair. In: Giannoudis PV, Einhorn TA, editors. Bone morphogenetic proteins: applications in orthopaedic and trauma surgery. Oxford (UK): Elsevier; 2010. p. 9–17.
  59. Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB. Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop. 2011;35(9):1271–80.

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