About this Journal Submit a Manuscript Table of Contents
BioMed Research International
Volume 2014 (2014), Article ID 239356, 11 pages
http://dx.doi.org/10.1155/2014/239356
Review Article

The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xiwu Road, Xi’an, Shaanxi 710004, China

Received 23 October 2013; Revised 23 January 2014; Accepted 16 February 2014; Published 11 May 2014

Academic Editor: Louise E. Glover

Copyright © 2014 Lihong Fan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Ema, K. Hirota, J. Mimura et al., “Molecular mechanisms of transcription activation by HLF and HIF1α in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300,” The EMBO Journal, vol. 18, no. 7, pp. 1905–1914, 1999. View at Scopus
  2. M. Nangaku, Y. Izuhara, S. Takizawa et al., “A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2548–2554, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Barth, J. Nesper, P. A. Hasgall et al., “The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability,” Molecular and Cellular Biology, vol. 27, no. 10, pp. 3758–3768, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. A. Danis, “Mechanism of bone lengthening by the Ilizarov technique,” Bulletin et Memoires de l"Academie Royale de Medecine de Belgique, vol. 156, no. 1-2, pp. 107–112, 2001. View at Scopus
  5. G. L. Wang, B.-H. Jiang, and G. L. Semenza, “Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1,” Biochemical and Biophysical Research Communications, vol. 216, no. 2, pp. 669–675, 1995. View at Publisher · View at Google Scholar · View at Scopus
  6. H. Li, H. P. Ko, and J. P. Whitlock Jr., “Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of Arnt and HIF1α,” Journal of Biological Chemistry, vol. 271, no. 35, pp. 21262–21267, 1996. View at Publisher · View at Google Scholar · View at Scopus
  7. G. L. Semenza, “Targeting HIF-1 for cancer therapy,” Nature Reviews Cancer, vol. 3, no. 10, pp. 721–732, 2003. View at Scopus
  8. W.-C. Hon, M. I. Wilson, K. Harlos et al., “Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL,” Nature, vol. 417, no. 6892, pp. 975–978, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. J.-H. Min, H. Yang, M. Ivan, F. Gertler, W. G. Kaelin Jr., and N. P. Pavietich, “Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling,” Science, vol. 296, no. 5574, pp. 1886–1889, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Ivan, K. Kondo, H. Yang et al., “HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing,” Science, vol. 292, no. 5516, pp. 464–468, 2001. View at Scopus
  11. P. Jaakkola, D. R. Mole, Y.-M. Tian et al., “Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation,” Science, vol. 292, no. 5516, pp. 468–472, 2001. View at Scopus
  12. N. Masson, C. Willam, P. H. Maxwell, C. W. Pugh, and P. J. Ratcliffe, “Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation,” The EMBO Journal, vol. 20, no. 18, pp. 5197–5206, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. P. H. Maxwell, M. S. Wlesener, G.-W. Chang et al., “The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis,” Nature, vol. 399, no. 6733, pp. 271–275, 1999. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Ohh, C. W. Park, M. Ivan et al., “Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel—lindau protein,” Nature Cell Biology, vol. 2, no. 7, pp. 423–427, 2000. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Hirsilä, P. Koivunen, V. Günzler, K. I. Kivirikko, and J. Myllyharju, “Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor,” Journal of Biological Chemistry, vol. 278, no. 33, pp. 30772–30780, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. N. Sang, J. Fang, V. Srinivas, I. Leshchinsky, and J. Caro, “Carboxyl-terminal transactivation activity of hypoxia-inducible factor 1α is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP,” Molecular and Cellular Biology, vol. 22, no. 9, pp. 2984–2992, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. Z. Arany, L. E. Huang, R. Eckner et al., “An essential role for p300/CBP in the cellular response to hypoxia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 23, pp. 12969–12973, 1996. View at Publisher · View at Google Scholar · View at Scopus
  18. R. H. Wenger, D. P. Stiehl, and G. Camenisch, “Integration of oxygen signaling at the consensus HRE,” Science's STKE, vol. 2005, no. 306, article re12, 2005. View at Scopus
  19. P. Koivunen, P. Tiainen, J. Hyvärinen et al., “An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor α,” Journal of Biological Chemistry, vol. 282, no. 42, pp. 30544–30552, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. A. C. R. Epstein, J. M. Gleadle, L. A. McNeill et al., “C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation,” Cell, vol. 107, no. 1, pp. 43–54, 2001. View at Publisher · View at Google Scholar · View at Scopus
  21. R. J. Appelhoffl, Y.-M. Tian, R. R. Raval et al., “Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor,” Journal of Biological Chemistry, vol. 279, no. 37, pp. 38458–38465, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. E. Metzen, D. P. Stiehl, K. Doege, J. H. Marxsen, T. Hellwig-Bürgel, and W. Jelkmann, “Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element,” Biochemical Journal, vol. 387, no. 3, pp. 711–717, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. N. Pescador, Y. Cuevas, S. Naranjo et al., “Identification of a functional hypoxia-responsive element that regulates the expression of the egl nine homologue 3 (egln3/phd3) gene,” Biochemical Journal, vol. 390, no. 1, pp. 189–197, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. J. H. Marxsen, P. Stengel, K. Doege et al., “Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases,” Biochemical Journal, vol. 381, no. 3, pp. 761–767, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. G. D'Angelo, E. Duplan, N. Boyer, P. Vigne, and C. Frelin, “Hypoxia up-regulates prolyl hydroxylase activity. A feedback mechansim that limits HIF-1 responses during reoxygenation,” Journal of Biological Chemistry, vol. 278, no. 40, pp. 38183–38187, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. D. P. Stiehl, R. Wirthner, J. Köditz, P. Spielmann, G. Camenisch, and R. H. Wenger, “Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels: evidence for an autoregulatory oxygen-sensing system,” Journal of Biological Chemistry, vol. 281, no. 33, pp. 23482–23491, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. C. J. Schofield and P. J. Ratcliffe, “Oxygen sensing by HIF hydroxylases,” Nature Reviews Molecular Cell Biology, vol. 5, no. 5, pp. 343–354, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. P. Hill, D. Shukla, M. G. B. Tran et al., “Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury,” Journal of the American Society of Nephrology, vol. 19, no. 1, pp. 39–46, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Eckle, D. Kohler, R. Lehmann, K. C. E. Kasmi, and H. K. Eltzschig, “Hypoxia-inducible factor-1 is central to cardioprotection a new paradigm for ischemic preconditioning,” Circulation, vol. 118, no. 2, pp. 166–175, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. E. P. Cummins, F. Seeballuck, S. J. Keely et al., “The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis,” Gastroenterology, vol. 134, no. 1, pp. 156–165, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Safran, W. Y. Kim, F. O'Connell et al., “Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 1, pp. 105–110, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Yan, V. J. Colandrea, and J. J. Hale, “Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia,” Expert Opinion on Therapeutic Patents, vol. 20, no. 9, pp. 1219–1245, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Schneider, G. Krischke, S. Keller et al., “Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain,” Brain Research, vol. 1280, pp. 43–51, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Rosenberger, S. Rosen, A. Shina et al., “Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney,” Nephrology Dialysis Transplantation, vol. 23, no. 11, pp. 3472–3478, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. W. Bao, P. Qin, S. Needle et al., “Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat,” Journal of Cardiovascular Pharmacology, vol. 56, no. 2, pp. 147–155, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. U. Hopfer, H. Hopfer, K. Jablonski, R. A. K. Stahl, and G. Wolf, “The novel WD-repeat protein Morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3),” Journal of Biological Chemistry, vol. 281, no. 13, pp. 8645–8655, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. L. Claesson-Welsh and M. Welsh, “VEGFA and tumour angiogenesis,” Journal of Internal Medicine, vol. 273, no. 2, pp. 114–127, 2013.
  38. Y.-X. Li, S.-J. Ding, L. Xiao, W. Guo, and Q. Zhan, “Desferoxamine preconditioning protects against cerebral ischemia in rats by inducing expressions of hypoxia inducible factor 1α and erythropoietin,” Neuroscience Bulletin, vol. 24, no. 2, pp. 89–95, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Hishikawa, S. Ono, T. Ogawa, K. Tokunaga, K. Sugiu, and I. Date, “Effects of deferoxamine-activated hypoxia-inducible factor-1 on the brainstem after subarachnoid hemorrhage in rats,” Neurosurgery, vol. 62, no. 1, pp. 232–240, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. X. Shen, C. Wan, G. Ramaswamy et al., “Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice,” Journal of Orthopaedic Research, vol. 27, no. 10, pp. 1298–1305, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. R. Stewart, J. Goldstein, A. Eberhardt, G. T.-M. Gabriel Chu, and S. Gilbert, “Increasing vascularity to improve healing of a segmental defect of the rat femur,” Journal of Orthopaedic Trauma, vol. 25, no. 8, pp. 472–476, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. W. Zhang, G. Li, R. Deng, L. Deng, and S. Qiu, “New bone formation in a true bone ceramic scaffold loaded with desferrioxamine in the treatment of segmental bone defect: a preliminary study,” Journal of Orthopaedic Science, vol. 17, no. 3, pp. 289–298, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Wan, S. R. Gilbert, Y. Wang, et al., “Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 2, pp. 686–691, 2008. View at Publisher · View at Google Scholar
  44. A. Donneys, S. S. Deshpande, C. N. Tchanque-Fossuo, et al., “Deferoxamine expedites consolidation during mandibular distraction osteogenesis,” Bone, vol. 55, no. 2, pp. 384–390, 2013. View at Publisher · View at Google Scholar
  45. L. Xi, M. Taher, C. Yin, F. Salloum, and R. C. Kukreja, “Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1α and AP-1 and iNOS signaling,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 287, no. 6, pp. H2369–H2375, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Philipp, L. Cui, B. Ludolph et al., “Desferoxamine and ethyl-3,4-dihydroxybenzoate protect myocardium by activating NOS and generating mitochondrial ROS,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 290, no. 1, pp. H450–H457, 2006. View at Publisher · View at Google Scholar · View at Scopus
  47. M. M. Hsieh, N. S. Linde, A. Wynter et al., “HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques,” Blood, vol. 110, no. 6, pp. 2140–2147, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. Q. Zhao, X. Shen, W. Zhang, G. Zhu, J. Qi, and L. Deng, “Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss,” Bone, vol. 50, no. 3, pp. 763–770, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. Y. Wang, C. Wan, S. R. Gilbert, and T. L. Clemens, “Oxygen sensing and osteogenesis,” Annals of the New York Academy of Sciences, vol. 1117, pp. 1–11, 2007.
  50. C. N. Rios, R. J. Skoracki, and A. B. Mathur, “GNAS1 and PHD2 short-interfering RNA support bone regeneration in vitro and in an in vivo sheep model,” Clinical Orthopaedics and Related Research, vol. 470, no. 9, pp. 2541–2553, 2012.
  51. R. Natarajan, F. N. Salloum, B. J. Fisher, R. C. Kukreja, and A. A. Fowler III, “Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury,” Circulation Research, vol. 98, no. 1, pp. 133–140, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. G. Czibik, J. Gravning, V. Martinov et al., “Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo,” Life Sciences, vol. 88, no. 11-12, pp. 543–550, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. T. Date, S. Mochizuki, A. J. Belanger et al., “Expression of constitutively stable hybrid hypoxia-inducible factor-1α protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury,” American Journal of Physiology—Cell Physiology, vol. 288, no. 2, pp. C314–C320, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. P. Tothill and J. N. MacPherson, “The distribution of blood flow to the whole skeleton in dogs, rabbits and rats measured with microspheres,” Clinical Physics and Physiological Measurement, vol. 7, no. 2, pp. 117–123, 1986. View at Publisher · View at Google Scholar · View at Scopus
  55. P. M. Gross, D. D. Heistad, and M. L. Marcus, “Neurohumoral regulation of blood flow to bones and marrow,” The American Journal of Physiology, vol. 237, no. 4, pp. H440–H448, 1979. View at Scopus
  56. R. C. Riddle, R. Khatri, E. Schipani, and T. L. Clemens, “Role of hypoxia-inducible factor-1α in angiogenic-osteogenic coupling,” Journal of Molecular Medicine, vol. 87, no. 6, pp. 583–590, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. G. L. Semenza, “Regulation of cancer cell metabolism by hypoxia-inducible factor 1,” Seminars in Cancer Biology, vol. 19, no. 1, pp. 12–16, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. E. Schipani, H. E. Ryan, S. Didrickson, T. Kobayashi, M. Knight, and R. S. Johnson, “Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival,” Genes and Development, vol. 15, no. 21, pp. 2865–2876, 2001. View at Scopus
  59. Y. Wang, C. Wan, L. Deng et al., “The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development,” Journal of Clinical Investigation, vol. 117, no. 6, pp. 1616–1626, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. C. C. Tsai, T. L. Yew, D. C. Yang, W. H. Huang, and S. C. Hung, “Benefits of hypoxic culture on bone marrow multipotent stromal cells,” American Journal of Blood Research, vol. 2, no. 3, pp. 148–159, 2012.
  61. C.-C. Tsai, Y.-J. Chen, T.-L. Yew et al., “Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST,” Blood, vol. 117, no. 2, pp. 459–469, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. S.-C. Hung, R. R. Pochampally, S.-C. Hsu et al., “Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo,” PLoS ONE, vol. 2, no. 5, article e416, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. H. Okuyama, B. Krishnamachary, Y. F. Zhou, H. Nagasawa, M. Bosch-Marce, and G. L. Semenza, “Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1,” Journal of Biological Chemistry, vol. 281, no. 22, pp. 15554–15563, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Fehrer, R. Brunauer, G. Laschober et al., “Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan,” Aging Cell, vol. 6, no. 6, pp. 745–757, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. C. Holzwarth, M. Vaegler, F. Gieseke et al., “Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells,” BMC Cell Biology, vol. 11, article 11, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. D.-C. Yang, M.-H. Yang, C.-C. Tsai, T.-F. Huang, Y.-H. Chen, and S.-C. Hung, “Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST,” PLoS ONE, vol. 6, no. 9, Article ID e23965, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Lord-Dufour, I. B. Copland, L.-C. Levros Jr. et al., “Evidence for transcriptional regulation of the glucose-6-phosphate transporter by HIF-1α: targeting G6PT with mumbaistatin analogs in hypoxic mesenchymal stromal cells,” Stem Cells, vol. 27, no. 3, pp. 489–497, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Penna, M.G. Perrelli, J. P. Karam, et al., “Pharmacologically active microcarriers influence VEGF-A effects on mesenchymal stem cell survival,” Journal of Cellular and Molecular Medicine, vol. 17, no. 1, pp. 192–204, 2013.
  69. B. Chen, Y.-B. Song, Y.-H. Li, and G.-X. Pei, “Effect of vascular endothelial growth factor gene transfer on proliferation and metabolism of human bone marrow stromal cells in vitro,” Nan Fang Yi Ke Da Xue Xue Bao, vol. 28, no. 7, pp. 1172–1175, 2008. View at Scopus
  70. J. Fiedler, F. Leucht, J. Waltenberger, C. Dehio, and R. E. Brenner, “VEGF-A and PlGF-1 stimulate chemotactic migration of human mesenchymal progenitor cells,” Biochemical and Biophysical Research Communications, vol. 334, no. 2, pp. 561–568, 2005. View at Publisher · View at Google Scholar · View at Scopus
  71. H. Lin, A. Shabbir, M. Molnar et al., “Adenoviral expression of vascular endothelial growth factor splice variants differentially regulate bone marrow-derived mesenchymal stem cells,” Journal of Cellular Physiology, vol. 216, no. 2, pp. 458–468, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. Z. Huang, P.-G. Ren, T. Ma, R. L. Smith, and S. B. Goodman, “Modulating osteogenesis of mesenchymal stem cells by modifying growth factor availability,” Cytokine, vol. 51, no. 3, pp. 305–310, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. Liu, A. D. Berendsen, S. Jia, et al., “Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation,” The Journal of Clinical Investigation, vol. 122, no. 9, pp. 3101–3113, 2012. View at Publisher · View at Google Scholar
  74. V. Midy and J. Plouet, “Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts,” Biochemical and Biophysical Research Communications, vol. 199, no. 1, pp. 380–386, 1994. View at Publisher · View at Google Scholar · View at Scopus
  75. U. Mayr-wohlfart, J. Waltenberger, H. Hausser et al., “Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts,” Bone, vol. 30, no. 3, pp. 472–477, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. R. Gruber, B. Kandler, P. Holzmann et al., “Bone marrow stromal cells can provide a local environment that favors migration and formation of tubular structures of endothelial cells,” Tissue Engineering, vol. 11, no. 5-6, pp. 896–903, 2005. View at Publisher · View at Google Scholar · View at Scopus
  77. I. A. Potapova, G. R. Gaudette, P. R. Brink et al., “Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro,” Stem Cells, vol. 25, no. 7, pp. 1761–1768, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. N. B. Thebaud, et al., “Whatever their differentiation status, human progenitor derived—or mature—endothelial cells induce osteoblastic differentiation of bone marrow stromal cells,” Journal of Tissue Engineering and Regenerative Medicine, vol. 6, no. 10, pp. e51–e60, 2012. View at Publisher · View at Google Scholar
  79. L. C. Gerstenfeld, D. M. Cullinane, G. L. Barnes, D. T. Graves, and T. A. Einhorn, “Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation,” Journal of Cellular Biochemistry, vol. 88, no. 5, pp. 873–884, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. Z. S. Al-Aql, A. S. Alagl, D. T. Graves, L. C. Gerstenfeld, and T. A. Einhorn, “Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis,” Journal of Dental Research, vol. 87, no. 2, pp. 107–118, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. I. H. Choi, J. H. Ahn, C. Y. Chung, and T.-J. Cho, “Vascular proliferation and blood supply during distraction osteogenesis: a scanning electron microscopic observation,” Journal of Orthopaedic Research, vol. 18, no. 5, pp. 698–705, 2000. View at Scopus
  82. D. E. Komatsu and M. Hadjiargyrou, “Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair,” Bone, vol. 34, no. 4, pp. 680–688, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Ferguson, E. Alpern, T. Miclau, and J. A. Helms, “Does adult fracture repair recapitulate embryonic skeletal formation?” Mechanisms of Development, vol. 87, no. 1-2, pp. 57–66, 1999. View at Publisher · View at Google Scholar · View at Scopus
  84. A. X. Le, T. Miclau, D. Hu, and J. A. Helms, “Molecular aspects of healing in stabilized and non-stabilized fractures,” Journal of Orthopaedic Research, vol. 19, no. 1, pp. 78–84, 2001. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Street, M. Bao, L. DeGuzman et al., “Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 15, pp. 9656–9661, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. T. Tarkka, A. Sipola, T. Jämsä et al., “Adenoviral VEGF-A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues,” Journal of Gene Medicine, vol. 5, no. 7, pp. 560–566, 2003. View at Publisher · View at Google Scholar · View at Scopus
  87. F. Geiger, H. Bertram, I. Berger et al., “Vascular endothelial growth factor gene-activated matrix (VEGF 165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects,” Journal of Bone and Mineral Research, vol. 20, no. 11, pp. 2028–2035, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. Y.-C. Huang, D. Kaigler, K. G. Rice, P. H. Krebsbach, and D. J. Mooney, “Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration,” Journal of Bone and Mineral Research, vol. 20, no. 5, pp. 848–857, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. X.-D. Liu, L.-F. Deng, J. Wang et al., “The regulation of hypoxia inducible factor-1alpha on osteoblast function in postmenopausal osteoporosis,” Zhonghua Wai Ke Za Zhi, vol. 45, no. 18, pp. 1274–1278, 2007. View at Scopus
  90. G. A. Ilizarov, “Clinical application of the tension-stress effect for limb lengthening,” Clinical Orthopaedics and Related Research, no. 250, pp. 8–26, 1990. View at Scopus
  91. K. A. Jacobsen, Z. S. Al-Aql, C. Wan et al., “Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling,” Journal of Bone and Mineral Research, vol. 23, no. 5, pp. 596–609, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. J. F. He, Z. J. Xie, H. Zhao et al., “Immunohistochemical and in-situ hybridization study of hypoxia inducible factor-1α and angiopoietin-1 in a rabbit model of mandibular distraction osteogenesis,” International Journal of Oral and Maxillofacial Surgery, vol. 37, no. 6, pp. 554–560, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. D. M. Pacicca, N. Patel, C. Lee et al., “Expression of angiogenic factors during distraction osteogenesis,” Bone, vol. 33, no. 6, pp. 889–898, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. Y. Yang, M. Sun, L. Wang, and B. Jiao, “HIFs, angiogenesis, and cancer,” Journal of Cellular Biochemistry, vol. 114, no. 5, pp. 967–974, 2013.
  95. M. M. Hickey and M. C. Simon, “Regulation of angiogenesis by hypoxia and hypoxia-inducible factors,” Current Topics in Developmental Biology, vol. 76, pp. 217–257, 2006. View at Publisher · View at Google Scholar · View at Scopus
  96. H. E. Ryan, J. Lo, and R. S. Johnson, “HIF-1α is required for solid tumor formation and embryonic vascularization,” The EMBO Journal, vol. 17, no. 11, pp. 3005–3015, 1998. View at Publisher · View at Google Scholar · View at Scopus
  97. Q. C. Yang, B. F. Zeng, Z. M. Shi et al., “Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma,” Journal of Experimental and Clinical Cancer Research, vol. 25, no. 4, pp. 593–599, 2006. View at Scopus
  98. Q. Wu, S.-H. Yang, R.-Y. Wang, S.-N. Ye, T. Xia, and D.-Z. Ma, “Effect of silencing HIF-1alpha by RNA interference on expression of vascular endothelial growth factor in osteosarcoma cell line SaOS-2 under hypoxia,” Chinese Journal of Cancer, vol. 24, no. 5, pp. 531–535, 2005. View at Scopus
  99. Q. Wu, S.-H. Yang, S.-N. Ye, and R.-Y. Wang, “Therapeutic effects of RNA interference targeting HIF-1 alpha gene on human osteosarcoma,” Zhonghua Yi Xue Za Zhi, vol. 85, no. 6, pp. 409–413, 2005. View at Scopus