The osteogenic-angiogenic interface: Novel insights into the biology of bone formation and fracture repair

Article

Abstract

Bone never forms without vascular interactions. Although this is a very simple and obvious statement, the biological, clinical, and pharmacologic implications are incompletely appreciated. The vasculature is not only the conduit for nutrient-metabolite exchange and the rate-limiting “point-of-reference” for Haversian bone formation, but also provides the sustentacular niche for the self-renewing osteoprogenitor. This past year, significant advances have been made in our understanding of the osteogenic-angiogenic interface that are immediately germane to osteoporosis disease biology and fracture management. The critical contributions of the osteoblast oxygen-sensing machinery, paracrine vascular endothelial growth factor and placental growth factor signaling, fracture-mobilized circulating osteoprogenitors, and the osteogenic CD146(+) marrow sinusoid stem cell have been recently discovered. This brief review recounts these revelations, highlighting the potential impact to human bone health and fracture repair.

References and Recommended Reading

  1. 1.
    Woolf AD, Pfleger B: Burden of major musculoskeletal conditions. Bull World Health Organ 2003, 81:646–656.PubMedGoogle Scholar
  2. 2.
    Zelzer E, McLean W, Ng YS, et al.: Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 2002, 129:1893–1904.PubMedGoogle Scholar
  3. 3.
    Carvalho RS, Einhorn TA, Lehmann W, et al.: The role of angiogenesis in a murine tibial model of distraction osteogenesis. Bone 2004, 34:849–861.PubMedCrossRefGoogle Scholar
  4. 4.
    Luo D, Luo Y, He Y, et al.: Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. Am J Pathol 2006, 169:1886–1898.PubMedCrossRefGoogle Scholar
  5. 5.
    He Y, Luo Y, Tang S, et al.: Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. J Clin Invest 2006, 116:2344–2355.PubMedGoogle Scholar
  6. 6.
    Wang Y, Wan C, Deng L, et al.: The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 2007, 117:1616–1626.PubMedCrossRefGoogle Scholar
  7. 7.
    Wan C, Gilbert SR, Wang Y, et al.: Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A 2008, 105:686–691.PubMedCrossRefGoogle Scholar
  8. 8.
    Zelzer E, Mamluk R, Ferrara N, et al.: VEGFA is necessary for chondrocyte survival during bone development. Development 2004, 131:2161–2171.PubMedCrossRefGoogle Scholar
  9. 9.
    Takahashi H, Shibuya M: The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 2005, 109:227–241.Google Scholar
  10. 10.
    Zelzer E, Glotzer DJ, Hartmann C, et al.: Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech Dev 2001, 106:97–106.PubMedCrossRefGoogle Scholar
  11. 11.
    Semenza GL, Wang GL: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992, 12:5447–5454.PubMedGoogle Scholar
  12. 12.
    Forsythe JA, Jiang BH, Iyer NV, et al.: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996, 16:4604–4613.PubMedGoogle Scholar
  13. 13.
    Semenza GL: HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 2001, 107:1–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Jaakkola P, Mole DR, Tian YM, et al.: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292:468–472.PubMedCrossRefGoogle Scholar
  15. 15.
    Towler DA: Vascular biology and bone formation: hints from HIF. J Clin Invest 2007, 117:1477–1480.PubMedCrossRefGoogle Scholar
  16. 16.
    Raaymakers EL: Fractures of the femoral neck: a review and personal statement. Acta Chir Orthop Traumatol Cech 2006, 73:45–59.PubMedGoogle Scholar
  17. 17.
    Thompson RC Jr, Clohisy DR: Deformity following fracture in diabetic neuropathic osteoarthropathy. Operative management of adults who have type-I diabetes. J Bone Joint Surg Am 1993, 75:1765–1773.PubMedGoogle Scholar
  18. 18.
    Ang E, Black C, Irish J, et al.: Reconstructive options in the treatment of osteoradionecrosis of the craniomaxillofacial skeleton. Br J Plast Surg 2003, 56:92–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Kalra S, McBryde CW, Lawrence T: Intracapsular hip fractures in end-stage renal failure. Injury 2006, 37:175–184.PubMedCrossRefGoogle Scholar
  20. 20.
    Damany DS, Parker MJ, Chojnowski A: Complications after intracapsular hip fractures in young adults. A meta-analysis of 18 published studies involving 564 fractures. Injury 2005, 36:131–141.PubMedGoogle Scholar
  21. 21.
    Khosla S, Burr D, Cauley J, et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007, 22:1479–1491.PubMedCrossRefGoogle Scholar
  22. 22.
    Aragones J, Schneider M, Van Geyte K, et al.: Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 2008, 40:170–180.PubMedCrossRefGoogle Scholar
  23. 23.
    Jorgensen NR, Schwarz P, Holme I, et al.: The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease: a cross sectional study. Respir Med 2007, 101:177–185.PubMedCrossRefGoogle Scholar
  24. 24.
    Fei F, Linnosier M, Laroche N, et al.: Chronic hypoxiainduced bone angiogenesis and reduction of bone marrow adipogenesis leads to bone loss in adult rats [abstract]. J Bone Miner Res 2006, 21:SA342.Google Scholar
  25. 25.
    Hauge EM, Qvesel D, Eriksen EF, et al.: Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res 2001, 16:1575–1582.PubMedCrossRefGoogle Scholar
  26. 26.
    Eriksen EF, Eghbali-Fatourechi GZ, Khosla S: Remodeling and vascular spaces in bone. J Bone Miner Res 2007, 22:1–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Parfitt AM: The bone remodeling compartment: a circulatory function for bone lining cells. J Bone Miner Res 2001, 16:1583–1585.PubMedCrossRefGoogle Scholar
  28. 28.
    Sacchetti B, Funari A, Michienzi S, et al.: Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007, 131:324–336.PubMedCrossRefGoogle Scholar
  29. 29.
    Shi S, Gronthos S: Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 2003, 18:696–704.PubMedCrossRefGoogle Scholar
  30. 30.
    Doherty MJ, Ashton BA, Walsh S, et al.: Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 1998, 13:828–838.PubMedCrossRefGoogle Scholar
  31. 31.
    Kolf CM, Cho E, Tuan RS: Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 2007, 9:204.PubMedCrossRefGoogle Scholar
  32. 32.
    Eghbali-Fatourechi GZ, Lamsam J, Fraser D, et al.: Circulating osteoblast-lineage cells in humans. N Engl J Med 2005, 352:1959–1966.PubMedCrossRefGoogle Scholar
  33. 33.
    Gazit D, Karmish M, Holzman L, Bab I: Regenerating marrow induces systemic increase in osteo-and chondrogenesis. Endocrinology 1990, 126:2607–2613.PubMedCrossRefGoogle Scholar
  34. 34.
    Eghbali-Fatourechi GZ, Modder UI, Charatcharoenwitthaya N, et al.: Characterization of circulating osteoblast lineage cells in humans. Bone 2007, 40:1370–1377.PubMedCrossRefGoogle Scholar
  35. 35.
    Traktuev DO, Merfeld-Clauss S, Li J, et al.: A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 2008, 102:77–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Matsumoto T, Kawamoto A, Kuroda R, et al.: Therapeutic potential of vasculogenesis and osteogenesis promoted by peripheral blood CD34-positive cells for functional bone healing. Am J Pathol 2006, 169:1440–1457.PubMedCrossRefGoogle Scholar
  37. 37.
    Matsumoto T, Mifune Y, Kawamoto A, et al.: Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing. J Cell Physiol 2008, 215:234–242.PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang H, Bradley A: Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 1996, 122:2977–2986.PubMedGoogle Scholar
  39. 39.
    Tsuji K, Bandyopadhyay A, Harfe BD, et al.: BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 2006, 38:1424–1429.PubMedCrossRefGoogle Scholar
  40. 40.
    Maes C, Coenegrachts L, Stockmans I, et al.: Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. J Clin Invest 2006, 116:1230–1242.PubMedCrossRefGoogle Scholar
  41. 41.
    Marrony S, Bassilana F, Seuwen K, Keller H: Bone morphogenetic protein 2 induces placental growth factor in mesenchymal stem cells. Bone 2003, 33:426–433.PubMedCrossRefGoogle Scholar
  42. 42.
    Raida M, Heymann AC, Gunther C, Niederwieser D: Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. Int J Mol Med 2006, 18:735–739.PubMedGoogle Scholar
  43. 43.
    Peng H, Usas A, Olshanski A, et al.: VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis. J Bone Miner Res 2005, 20:2017–2027.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Internal Medicine-BMDWashington University School of MedicineSt. LouisUSA

Personalised recommendations