Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-29T05:51:09.344Z Has data issue: false hasContentIssue false
  • English
  • Français

Hypoxia signalling manipulation for bone regeneration

Published online by Cambridge University Press:  22 April 2015

Justin Drager ,
Edward J. Harvey  and
Jake Barralet
Justin Drager
Affiliation:
Division of Orthopaedic Surgery, McGill University Health Centre, Montreal, Quebec, Canada
Edward J. Harvey
Affiliation:
Division of Orthopaedic Surgery, McGill University Health Centre, Montreal, Quebec, Canada
Jake Barralet*
Affiliation:
Division of Orthopaedic Surgery, McGill University Health Centre, Montreal, Quebec, Canada
*
*Corresponding author: Division of Orthopaedic Surgery, Montreal General Hospital L9-125, 1650 Cedar Avenue, Montreal Quebec, CanadaH3G 1A4. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Hypoxia-inducible factor (HIF) signalling is intricately involved in coupling angiogenesis and osteogenesis during bone development and repair. Activation of HIFs in response to a hypoxic bone micro-environment stimulates the transcription of multiple genes with effects on angiogenesis, precursor cell recruitment and differentiation. Substantial progress has been made in our understanding of the molecular mechanisms by which oxygen content regulates the levels and activity of HIFs. In particular, the discovery of the role of oxygen-dependent hydroxylase enzymes in modulating the activity of HIF-1α has sparked interest in potentially promising therapeutic strategies in multiple clinical fields and most recently bone healing. Several small molecules, termed hypoxia mimics, have been identified as activators of the HIF pathway and have demonstrated augmentation of both bone vascularity and bone regeneration in vivo. In this review we discuss key elements of the hypoxic signalling pathway and its role in bone regeneration. Current strategies for the manipulation of this pathway for enhancing bone repair are presented with an emphasis on recent pre-clinical in vivo investigations. These findings suggest promising approaches for the development of therapies to improve bone repair and tissue engineering strategies.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 17 , 2015 , e6
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Wang, Y. et al. (2007) Oxygen sensing and osteogenesis. Annals of the New York Academy of Sciences 1117, 1-11 CrossRefGoogle ScholarPubMed
2. Schipani, E. et al. (2009) Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. Journal of Bone and Mineral Research 24, 1347-1353 CrossRefGoogle ScholarPubMed
3. Keramaris, N.C. et al. (2008) Fracture vascularity and bone healing: a systematic review of the role of VEGF. Injury 39, S45-S57 CrossRefGoogle ScholarPubMed
4. Maes, C., Carmeliet, G. and Schipani, E. (2012) Hypoxia-driven pathways in bone development, regeneration and disease. Nature Reviews Rheumatology 8, 358-366 CrossRefGoogle ScholarPubMed
5. Riddle, R.C. et al. (2009) Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. Journal of Molecular Medicine (Berlin) 87, 583-590 CrossRefGoogle ScholarPubMed
6. Arnett, T.R. (2010) Acidosis, hypoxia and bone. Archives of Biochemistry and Biophysics 503, 103-109 CrossRefGoogle ScholarPubMed
7. Wang, G.L. and Semenza, G.L. (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America 90, 4304-4308 CrossRefGoogle ScholarPubMed
8. Wan, C. et al. (2010) Role of HIF-1alpha in skeletal development. Annals of the New York Academy of Sciences 1192, 322-326 CrossRefGoogle ScholarPubMed
9. Jaakkola, P. et al. (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468-472 CrossRefGoogle Scholar
10. Maxwell, P.H. et al. (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271-275 CrossRefGoogle ScholarPubMed
11. Kallio, P.J. et al. (1999) Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. Journal of Biological Chemistry 274, 6519-6525 CrossRefGoogle ScholarPubMed
12. Kallio, P.J. et al. (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proceedings of the National Academy of Sciences of the United States of America 94, 5667-5672 CrossRefGoogle ScholarPubMed
13. Gu, J., Milligan, J. and Huang, L.E. (2001) Molecular mechanism of hypoxia-inducible factor 1alpha -p300 interaction. A leucine-rich interface regulated by a single cysteine. Journal of Biological Chemistry 276, 3550-3554 CrossRefGoogle ScholarPubMed
14. Lando, D. et al. (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295, 858-861 CrossRefGoogle ScholarPubMed
15. Greijer, A.E. et al. (2005) Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). Journal of Pathology 206, 291-304 CrossRefGoogle ScholarPubMed
16. Schofield, C.J. and Ratcliffe, P.J. (2004) Oxygen sensing by HIF hydroxylases. Nature Reviews Molecular Cell Biology 5, 343-354 CrossRefGoogle ScholarPubMed
17. Nagel, S. et al. (2010) Therapeutic manipulation of the HIF hydroxylases. Antioxidants and Redox Signaling 12, 481-501 CrossRefGoogle ScholarPubMed
18. Keith, B., Johnson, R.S. and Simon, M.C. (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature Reviews Cancer 12, 9-22 CrossRefGoogle Scholar
19. Hu, C.J. et al. (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Molecular and Cellular Biology 23, 9361-9374 CrossRefGoogle ScholarPubMed
20. Makino, Y. et al. (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550-554 CrossRefGoogle ScholarPubMed
21. Hara, S. et al. (2001) Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochemical and Biophysical Research Communications 287, 808-813 CrossRefGoogle ScholarPubMed
22. Zelzer, E. and Olsen, B.R. (2005) Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Current Topics in Developmental Biology 65, 169-187 CrossRefGoogle ScholarPubMed
23. Maes, C. et al. (2010) Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Developmental Cell 19, 329-344 CrossRefGoogle Scholar
24. Claes, L., Recknagel, S. and Ignatius, A. (2012) Fracture healing under healthy and inflammatory conditions. Nature Reviews Rheumatology 8, 133-143 CrossRefGoogle ScholarPubMed
25. Gerstenfeld, L.C. et al. (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. Journal of Cellular Biochemistry 88, 873-884 CrossRefGoogle ScholarPubMed
26. Gerber, H.P. et al. (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Medicine 5, 623-628 CrossRefGoogle ScholarPubMed
27. Street, J. et al. (2002) 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 99, 9656-9661 CrossRefGoogle ScholarPubMed
28. Geiger, F. et al. (2005) Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. Journal of Bone and Mineral Research 20, 2028-2035 CrossRefGoogle ScholarPubMed
29. Crisan, M. et al. (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301-313 CrossRefGoogle ScholarPubMed
30. Corselli, M. et al. (2012) The tunica adventitia of human arteries and veins as a source of mesenchymal stem cells. Stem Cells and Development 21, 1299-1308 CrossRefGoogle ScholarPubMed
31. Sacchetti, B. et al. (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324-336 CrossRefGoogle ScholarPubMed
32. le Noble, F. and le Noble, J. (2014) Bone biology: vessels of rejuvenation. Nature 507, 313-314 CrossRefGoogle ScholarPubMed
33. Wan, C. et al. (2008) Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proceedings of the National Academy of Sciences of the United States of America 105, 686-691 CrossRefGoogle ScholarPubMed
34. Brighton, C.T. and Heppenstall, R.B. (1971) Oxygen tension in zones of the epiphyseal plate, the metaphysis and diaphysis. An in vitro and in vivo study in rats and rabbits. Journal of Bone and Joint Surgery – A 53, 719-728 CrossRefGoogle Scholar
35. Brighton, C.T. and Krebs, A.G. (1972) Oxygen tension of healing fractures in the rabbit. Journal of Bone and Joint Surgery – A 54 323-332 CrossRefGoogle ScholarPubMed
36. Provot, S. et al. (2007) Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development. Journal of Cell Biology 177, 451-464 CrossRefGoogle ScholarPubMed
37. Wang, Y. et al. (2007) The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. Journal of Clinical Investigation 117, 1616-1626 CrossRefGoogle ScholarPubMed
38. Pfander, D. et al. (2003) HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. Journal of Cell Science 116(Pt 9), 1819-1826 CrossRefGoogle ScholarPubMed
39. Shomento, S.H. et al. (2010) Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development. Journal of Cellular Biochemistry 109, 196-204 CrossRefGoogle ScholarPubMed
40. Saito, T. et al. (2010) Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nature Medicine 16, 678-686 CrossRefGoogle ScholarPubMed
41. Araldi, E. et al. (2011) Lack of HIF-2alpha in limb bud mesenchyme causes a modest and transient delay of endochondral bone development. Nature Medicine 17, 25-26; author reply 27-9CrossRefGoogle ScholarPubMed
42. Amarilio, R. et al. (2007) HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development 134, 3917-3928 CrossRefGoogle ScholarPubMed
43. Komatsu, D.E. and Hadjiargyrou, M. (2004) Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. Bone 34, 680-688 CrossRefGoogle ScholarPubMed
44. Kusumbe, A.P., Ramasamy, S.K. and Adams, R.H. (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323-328 CrossRefGoogle ScholarPubMed
45. Liu, Y. et al. (2012) Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. Journal of Clinical Investigation 122, 3101-3113 CrossRefGoogle ScholarPubMed
46. Ceradini, D.J. et al. (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine 10, 858-864 CrossRefGoogle ScholarPubMed
47. Kitaori, T. et al. (2009) Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis and Rheumatism 60, 813-823 CrossRefGoogle Scholar
48. Marquez-Curtis, L.A. and Janowska-Wieczorek, A. (2013) Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomedical Research International 2013, 561098 CrossRefGoogle ScholarPubMed
49. Otsuru, S. et al. (2008) Circulating bone marrow-derived osteoblast progenitor cells are recruited to the bone-forming site by the CXCR4/stromal cell-derived factor-1 pathway. Stem Cells 26, 223-234 CrossRefGoogle Scholar
50. Liu, Y.S. et al. (2014) The effect of simvastatin on chemotactic capability of SDF-1alpha and the promotion of bone regeneration. Biomaterials 35(15), 4489-4498 CrossRefGoogle ScholarPubMed
51. Ceradini, D.J. and Gurtner, G.C. (2005) Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends in Cardiovascular Medicine 15, 57-63 CrossRefGoogle ScholarPubMed
52. Staller, P. et al. (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307-311 CrossRefGoogle ScholarPubMed
53. Hirao, M. et al. (2007) Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes. Journal of Bone and Mineral Metabolism 25, 266-276 CrossRefGoogle ScholarPubMed
54. Utting, J.C. et al. (2006) Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts. Experimental Cell Research 312, 1693-1702 CrossRefGoogle ScholarPubMed
55. Steinbrech, D.S. et al. (1999) Hypoxia regulates VEGF expression and cellular proliferation by osteoblasts in vitro. Plastic and Reconstructive Surgery 104, 738-747 CrossRefGoogle ScholarPubMed
56. Matsuda, N. et al. (1998) Proliferation and differentiation of human osteoblastic cells associated with differential activation of MAP kinases in response to epidermal growth factor, hypoxia, and mechanical stress in vitro. Biochemical and Biophysical Research Communications 249, 350-354 CrossRefGoogle ScholarPubMed
57. Genetos, D.C. et al. (2010) Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. Journal of Cellular Biochemistry 110, 457-467 CrossRefGoogle ScholarPubMed
58. Chen, D. et al. (2013) HIF-1alpha inhibits Wnt signaling pathway by activating Sost expression in osteoblasts. PLoS ONE 8, e65940 Google ScholarPubMed
59. Ito, H. et al. (2005) Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nature Medicine 11, 291-297 CrossRefGoogle ScholarPubMed
60. Arnett, T.R. et al. (2003) Hypoxia is a major stimulator of osteoclast formation and bone resorption. Journal of Cellular Physiology 196, 2-8 CrossRefGoogle Scholar
61. Utting, J.C. et al. (2010) Hypoxia stimulates osteoclast formation from human peripheral blood. Cell Biochemistry and Function 28, 374-380 CrossRefGoogle ScholarPubMed
62. Knowles, H.J. and Athanasou, N.A. (2009) Acute hypoxia and osteoclast activity: a balance between enhanced resorption and increased apoptosis. Journal of Pathology 218, 256-264 CrossRefGoogle ScholarPubMed
63. Knowles, H.J. et al. (2010) Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB Journal 24, 4648-4659 Google ScholarPubMed
64. Leger, A.J. et al. (2010) Inhibition of osteoclastogenesis by prolyl hydroxylase inhibitor dimethyloxallyl glycine. Journal of Bone and Mineral Metabolism 28, 510-519 CrossRefGoogle ScholarPubMed
65. Indo, Y. et al. (2013) Metabolic regulation of osteoclast differentiation and function. Journal of Bone and Mineral Research 28, 2392-2399 CrossRefGoogle ScholarPubMed
66. Huang, W. et al. (1998) Use of intrinsic modes in biology: examples of indicial response of pulmonary blood pressure to +/− step hypoxia. Proceedings of the National Academy of Sciences of the United States of America 95, 12766-12771 CrossRefGoogle ScholarPubMed
67. Mahon, P.C., Hirota, K. and Semenza, G.L. (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes & Development 15, 2675-2686 CrossRefGoogle Scholar
68. Zou, D. et al. (2012) Blood vessel formation in the tissue-engineered bone with the constitutively active form of HIF-1alpha mediated BMSCs. Biomaterials 33, 2097-2108 CrossRefGoogle ScholarPubMed
69. Zou, D. et al. (2011) Repairing critical-sized calvarial defects with BMSCs modified by a constitutively active form of hypoxia-inducible factor-1alpha and a phosphate cement scaffold. Biomaterials 32, 9707-9718 CrossRefGoogle Scholar
70. Zou, D. et al. (2011) Repair of critical-sized rat calvarial defects using genetically engineered bone marrow-derived mesenchymal stem cells overexpressing hypoxia-inducible factor-1alpha. Stem Cells 29, 1380-1390 CrossRefGoogle ScholarPubMed
71. Ding, H. et al. (2013) HIF-1alpha transgenic bone marrow cells can promote tissue repair in cases of corticosteroid-induced osteonecrosis of the femoral head in rabbits. PLoS ONE 8, e63628 Google ScholarPubMed
72. Ma, T. (2010) Mesenchymal stem cells: from bench to bedside. World Journal of Stem Cells 2, 13-17 CrossRefGoogle ScholarPubMed
73. Murray, I.R. et al. (2014) Recent insights into the identity of mesenchymal stem cells: implications for orthopaedic applications. Bone & Joint Journal 96-B, 291-298 CrossRefGoogle ScholarPubMed
74. Aprelikova, O. et al. (2004) Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. Journal of Cellular Biochemistry 92, 491-501 CrossRefGoogle ScholarPubMed
75. Gleadle, J.M. et al. (1995) Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. American Journal of Physiology 268(6 Pt 1), C1362-C1368 CrossRefGoogle ScholarPubMed
76. Flagg, S.C. et al. (2012) Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH). Journal of Inorganic Biochemistry 113, 25-30 CrossRefGoogle ScholarPubMed
77. Cho, E.A. et al. (2013) Differential in vitro and cellular effects of iron chelators for hypoxia inducible factor hydroxylases. Journal of Cellular Biochemistry 114, 864-873 CrossRefGoogle ScholarPubMed
78. Li, Y.X. et al. (2008) Desferoxamine preconditioning protects against cerebral ischemia in rats by inducing expressions of hypoxia inducible factor 1 alpha and erythropoietin. Neuroscience Bulletin 24, 89-95 CrossRefGoogle ScholarPubMed
79. Hamrick, S.E. et al. (2005) A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection. Neuroscience Letters 379, 96-100 CrossRefGoogle ScholarPubMed
80. Chekanov, V.S. et al. (2003) Deferoxamine-fibrin accelerates angiogenesis in a rabbit model of peripheral ischemia. Vascular Medicine 8, 157-162 CrossRefGoogle Scholar
81. Shen, X. et al. (2009) Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. Journal of Orthopaedic Research 27, 1298-1305 CrossRefGoogle ScholarPubMed
82. Donneys, A. et al. (2012) Deferoxamine enhances the vascular response of bone regeneration in mandibular distraction osteogenesis. Plastic and Reconstructive Surgery 129, 850-856 CrossRefGoogle ScholarPubMed
83. Donneys, A. et al. (2013) Deferoxamine expedites consolidation during mandibular distraction osteogenesis. Bone 55, 384-390 CrossRefGoogle ScholarPubMed
84. Farberg, A.S. et al. (2012) Deferoxamine reverses radiation induced hypovascularity during bone regeneration and repair in the murine mandible. Bone 50, 1184-1187 CrossRefGoogle ScholarPubMed
85. Felice, P.A. et al. (2013) Deferoxamine administration delivers translational optimization of distraction osteogenesis in the irradiated mandible. Plastic and Reconstructive Surgery 132, 542e-548e CrossRefGoogle ScholarPubMed
86. Donneys, A. et al. (2013) Deferoxamine restores callus size, mineralization, and mechanical strength in fracture healing after radiotherapy. Plastic and Reconstructive Surgery 131, 711e-719e CrossRefGoogle ScholarPubMed
87. Donneys, A. et al. (2013) Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy. Bone 52, 318-325 CrossRefGoogle ScholarPubMed
88. Stewart, R. et al. (2011) Increasing vascularity to improve healing of a segmental defect of the rat femur. Journal of Orthopaedic Trauma 25, 472-476 CrossRefGoogle ScholarPubMed
89. Zhang, W. et al. (2012) 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 17, 289-298 CrossRefGoogle Scholar
90. Hertzberg, B.P. et al. (2013) An evaluation of carrier agents for desferoxamine, an up-regulator of vascular endothelial growth factor. Journal of Biomaterials Application 27, 1046-1054 CrossRefGoogle ScholarPubMed
91. MacKenzie, E.L., Iwasaki, K. and Tsuji, Y. (2008) Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxidants & Redox Signaling 10, 997-1030 CrossRefGoogle ScholarPubMed
92. Lloyd, J.B., Cable, H. and Rice-Evans, C. (1991) Evidence that desferrioxamine cannot enter cells by passive diffusion. Biochemical Pharmacology 41, 1361-1363 CrossRefGoogle ScholarPubMed
93. Doorn, J. et al. (2013) A small molecule approach to engineering vascularized tissue. Biomaterials 34, 3053-3063 CrossRefGoogle ScholarPubMed
94. Cunningham, M.J. et al. (2004) Complications of beta-thalassemia major in North America. Blood 104, 34-39 CrossRefGoogle ScholarPubMed
95. Vogiatzi, M.G. et al. (2009) Bone disease in thalassemia: a frequent and still unresolved problem. Journal of Bone and Mineral Research 24, 543-557 CrossRefGoogle ScholarPubMed
96. Fung, E.B. et al. (2008) Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia. Bone 43, 162-168 CrossRefGoogle ScholarPubMed
97. Wong, P. et al. (2013) Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures. Osteoporosis International 24, 1965-1971 CrossRefGoogle ScholarPubMed
98. Kim, B.J. et al. (2012) Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. Journal of Bone and Mineral Research 27, 2279-2290 CrossRefGoogle Scholar
99. Tsay, J. et al. (2010) Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116, 2582-2589 CrossRefGoogle Scholar
100. Chen, B. et al. (2014) Therapeutic effect of deferoxamine on iron overload-induced inhibition of osteogenesis in a zebrafish model. Calcified Tissue International 94, 353-360 CrossRefGoogle Scholar
101. Olivieri, N.F. et al. (1992) Growth failure and bony changes induced by deferoxamine. American Journal of Pediatric Hematology and Oncology 14, 48-56 CrossRefGoogle ScholarPubMed
102. Hartkamp, M.J., Babyn, P.S. and Olivieri, F. (1993) Spinal deformities in deferoxamine-treated homozygous beta-thalassemia major patients. Pediatric Radiology 23, 525-528 CrossRefGoogle ScholarPubMed
103. Wong, P. et al. (2014) Thalassemia bone disease: a 19 year longitudinal analysis. Journal of Bone and Mineral Research 29(11), 2468-2473 CrossRefGoogle ScholarPubMed
104. Cunliffe, C.J. et al. (1992) Novel inhibitors of prolyl 4-hydroxylase. 3. Inhibition by the substrate analog N-oxaloglycine and its derivatives. Journal of Medicinal Chemistry 35, 2652-2658 CrossRefGoogle ScholarPubMed
105. Ding, H. et al. (2014) Dimethyloxaloylglycine increases the bone healing capacity of adipose-derived stem cells by promoting osteogenic differentiation and angiogenic potential. Stem Cells and Development 23(9), 990-1000 CrossRefGoogle ScholarPubMed
106. Wu, C. et al. (2012) Hypoxia-mimicking mesoporous bioactive glass scaffolds with controllable cobalt ion release for bone tissue engineering. Biomaterials 33, 2076-2085 CrossRefGoogle ScholarPubMed
107. Fan, W., Crawford, R. and Xiao, Y. (2010) Enhancing in vivo vascularized bone formation by cobalt chloride-treated bone marrow stromal cells in a tissue engineered periosteum model. Biomaterials 31, 3580-3589 CrossRefGoogle Scholar
108. Patntirapong, S., Habibovic, P. and Hauschka, P.V. (2009) Effects of soluble cobalt and cobalt incorporated into calcium phosphate layers on osteoclast differentiation and activation. Biomaterials 30, 548-555 CrossRefGoogle ScholarPubMed
109. Dorr, L.D. et al. (1990) Histologic, biochemical, and ion analysis of tissue and fluids retrieved during total hip arthroplasty. Clinical Orthopaedics and Related Research 82-95 Google ScholarPubMed
110. Urban, R.M. et al. (1994) Migration of corrosion products from modular hip prostheses. Particle microanalysis and histopathological findings. Journal of Bone & Joint Surgery 76, 1345-1359 CrossRefGoogle ScholarPubMed
111. Patntirapong, S. and Hauschka, P.V. (2007) Molecular regulation of bone resorption by hypoxia. Orthopedic Journal of HMS 9, 72-75 Google Scholar
112. Patntirapong, S., Sharma, P. and Hauschka, P. (2007) Induction of osteoclast differentiation and resorptive activity by hypoxia and cobalt. Orthopedic Research Society Paper No. 298Google Scholar
113. Kung, A.L. et al. (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6, 33-43 CrossRefGoogle ScholarPubMed
114. Maes, C. et al. (2010) Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO Journal 29, 424-441 CrossRefGoogle ScholarPubMed
115. Hong, W.X. et al. (2014) The Role of Hypoxia-Inducible Factor in Wound Healing. Advantage Wound Care (New Rochelle) 3, 390-399 CrossRefGoogle ScholarPubMed
116. Distler, J.H. et al. (2007) Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis and Rheumatism 56, 4203-4215 CrossRefGoogle ScholarPubMed
117. Semenza, G.L. et al. (1991) Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America 88, 5680-5684 CrossRefGoogle Scholar
118. Yan, L., Colandrea, V.J. and Hale, J.J. (2010) Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia. Expert Opinion on Therapeutic Patents 20, 1219-1245 CrossRefGoogle ScholarPubMed
119. Haase, V.H. (2010) Hypoxic regulation of erythropoiesis and iron metabolism. American Journal of Physiology – Renal Physiology 299, F1-F13 CrossRefGoogle ScholarPubMed
120. Rankin, E.B. et al. (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149, 63-74 CrossRefGoogle ScholarPubMed
121. Bertout, J.A., Patel, S.A. and Simon, M.C. (2008) The impact of O2 availability on human cancer. Nature Reviews Cancer 8, 967-975 CrossRefGoogle ScholarPubMed
122. Semenza, G.L. (2003) Targeting HIF-1 for cancer therapy. Nature Reviews Cancer 3, 721-732 CrossRefGoogle ScholarPubMed
123. Hu, Y., Liu, J. and Huang, H. (2013) Recent agents targeting HIF-1alpha for cancer therapy. Journal of Cellular Biochemistry 114, 498-509 CrossRefGoogle ScholarPubMed
124. Rapisarda, A. et al. (2002) Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Research 62, 4316-4324 Google ScholarPubMed
125. Li, Y. and Ye, D. (2010) Cancer therapy by targeting hypoxia-inducible factor-1. Current Cancer Drug Targets 10, 782-796 CrossRefGoogle ScholarPubMed
126. Wilson, W.R. and Hay, M.P. (2011) Targeting hypoxia in cancer therapy. Nature Reviews Cancer 11, 393-410 CrossRefGoogle ScholarPubMed
127. Yang, Q.C. et al. (2007) Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome. Japanese Journal of Clinical Oncology 37, 127-134 CrossRefGoogle ScholarPubMed
128. Chen, W.L., Feng, H.J. and Li, H.G. (2008) Expression and significance of hypoxemia-inducible factor-1alpha in osteosarcoma of the jaws. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology & Endodontics Oral 106, 254-257 CrossRefGoogle ScholarPubMed
129. Guo, M. et al. (2014) Hypoxia promotes migration and induces CXCR4 expression via HIF-1alpha activation in human osteosarcoma. PLoS ONE 9, e90518 Google ScholarPubMed
130. Ishikawa, T. et al. (2009) Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncology Reports 21, 707-712 Google ScholarPubMed
131. Liu, Y.L. et al. (2006) Regulation of the chemokine receptor CXCR4 and metastasis by hypoxia-inducible factor in non small cell lung cancer cell lines. Cancer Biology & Therapy 5, 1320-1326 CrossRefGoogle ScholarPubMed
132. Guan, G. et al. (2014) The HIF-1alpha/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells. Cancer Letters 357(1), 254-264 CrossRefGoogle ScholarPubMed
133. Roncuzzi, L., Pancotti, F. and Baldini, N. (2014) Involvement of HIF-1alpha activation in the doxorubicin resistance of human osteosarcoma cells. Oncology Reports 32, 389-394 CrossRefGoogle ScholarPubMed
134. Unwith, S. et al. (2014) The potential role of HIF on tumour progression and dissemination. International Journal of Cancer (in press), doi:10.1002/ijc.28889Google ScholarPubMed
135. Smith, K.J. et al. (2003) The cardiovascular effects of erythropoietin. Cardiovascular Research 59, 538-548 CrossRefGoogle ScholarPubMed
136. Nangaku, M. et al. (2007) A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology 27, 2548-2554 CrossRefGoogle ScholarPubMed
137. Kontani, S. et al. (2013) A novel prolyl hydroxylase inhibitor protects against cell death after hypoxia. Neurochemical Research 38, 2588-2594 CrossRefGoogle ScholarPubMed