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Current Osteoporosis Reports

, Volume 17, Issue 1, pp 26–35 | Cite as

Hypoxia Signaling in the Skeleton: Implications for Bone Health

  • Clare E. Yellowley
  • Damian C. GenetosEmail author
Skeletal Biology and Regulation (M Forwood and A Robling, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Biology and Regulation

Abstract

Purpose of Review

We reviewed recent literature on oxygen sensing in osteogenic cells and its contribution to development of a skeletal phenotype, the coupling of osteogenesis with angiogenesis and integration of hypoxia into canonical Wnt signaling, and opportunities to manipulate oxygen sensing to promote skeletal repair.

Recent Findings

Oxygen sensing in osteocytes can confer a high bone mass phenotype in murine models; common and unique targets of HIF-1α and HIF-2α and lineage-specific deletion of oxygen sensing machinery suggest differentia utilization and requirement of HIF-α proteins in the differentiation from mesenchymal stem cell to osteoblast to osteocyte; oxygen-dependent but HIF-α-independent signaling may contribute to observed skeletal phenotypes.

Summary

Manipulating oxygen sensing machinery in osteogenic cells influences skeletal phenotype through angiogenesis-dependent and angiogenesis-independent pathways and involves HIF-1α, HIF-2α, or both proteins. Clinically, an FDA-approved iron chelator promotes angiogenesis and osteogenesis, thereby enhancing the rate of fracture repair.

Keywords

Bone Hypoxia Wnt Sclerostin HIF 

Notes

Acknowledgements

We are grateful to those whose work was cited within and to those whose work was not due to space limitations. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award R01AR064255 (DCG).

Compliance with Ethical Standards

Conflict of Interest

Clare Yellowley and Damian Genetos declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Monahan-Earley R, Dvorak AM, Aird WC. Evolutionary origins of the blood vascular system and endothelium. J Thromb Haemost. Wiley/Blackwell (10.1111); 2013;11 Suppl 1:46–66.Google Scholar
  2. 2.
    Dunwoodie SL. The role of hypoxia in development of the Mammalian embryo. Dev Cell. 2009;17:755–73.CrossRefPubMedGoogle Scholar
  3. 3.
    Hu C-J, Sataur A, Wang L, Chen H, Simon MC. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Tansey W, editor. Mol Biol Cell. 2007;18:4528–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Pawlus MR, Hu C-J. Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response. Cell Signal. 2013;25:1895–903.CrossRefPubMedGoogle Scholar
  5. 5.
    Koivunen P, Hirsila M, Gunzler V, Kivirikko KI, Myllyharju J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. American Society for Biochemistry and Molecular Biology. 2004;279:9899–904.Google Scholar
  6. 6.
    Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci. 2012;37:364–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Lin Q, Cong X, Yun Z. Differential Hypoxic Regulation of Hypoxia-Inducible Factors 1α and 2α. Mol Cancer Res. American Association for Cancer Research. 2011;9:757–65.Google Scholar
  8. 8.
    Stegen S, Carmeliet G. The skeletal vascular system – Breathing life into bone tissue. Bone. Elsevier. 2018;115:50–8.CrossRefGoogle Scholar
  9. 9.
    Brighton CT, Krebs AG. Oxygen tension of healing fractures in the rabbit. J Bone Joint Surg Am. 1972;54:323–32.CrossRefPubMedGoogle Scholar
  10. 10.
    Harrison JS, Rameshwar P, Chang V, Bandari P. Oxygen saturation in the bone marrow of healthy volunteers. Blood. American Society of Hematology. 2002;99:394–4.Google Scholar
  11. 11.
    Dodd JS, Raleigh JA, Gross TS. Osteocyte hypoxia: a novel mechanotransduction pathway. Am J Physiol. 1999;277:C598–602.CrossRefPubMedGoogle Scholar
  12. 12.
    Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507:323–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development. Oxford University Press for The Company of Biologists Limited; 2016;143:2706–2715.Google Scholar
  14. 14.
    Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. Nature Publishing Group. 2014;508:269–73.Google Scholar
  15. 15.
    Guo D, Keightley A, Guthrie J, Veno PA, Harris SE, Bonewald LF. Identification of osteocyte-selective proteins. Huber C, Huber L, editors. Proteomics. Wiley-Blackwell; 2010;10:3688–3698.Google Scholar
  16. 16.
    Frikha-Benayed D, Basta Pljakic J, Majeska RJ, Schaffler MB. Regional differences in oxidative metabolism and mitochondrial activity among cortical bone osteocytes. Bone. Elsevier Inc. 2016;90:15–22.Google Scholar
  17. 17.
    Mangiavini L, Merceron C, Araldi E, Khatri R, Gerard-O'Riley R, Wilson TL, et al. Loss of VHL in mesenchymal progenitors of the limb bud alters multiple steps of endochondral bone development. Dev Biol. 2014;393:124–36.CrossRefPubMedGoogle Scholar
  18. 18.
    Cheng S, Aghajanian P, Pourteymoor S, Alarcon C, Mohan S. Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Regulates Chondrocyte Differentiation and Secondary Ossification in Mice. Sci Rep. 2016;6:35748.CrossRefPubMedGoogle Scholar
  19. 19.
    Weng T, Xie Y, Huang J, Luo F, Yi L, He Q, et al. Inactivation of Vhl in osteochondral progenitor cells causes high bone mass phenotype and protects against age-related bone loss in adult mice. J Bone Miner Res. 2014;29:820–9.CrossRefPubMedGoogle Scholar
  20. 20••.
    Wu C, Rankin EB, Castellini L, Alcudia JF, Fernandez-Alcudia J, LaGory EL, et al. Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. Genes Dev. Cold Spring Harbor Lab; 2015;29:817–31. Deletion of individual PHD proteins in osteoprogenitors is insufficient to produce a high bone mass phenotype; high bone mass phenotypes can occur independent of changes in bone vascularity. Google Scholar
  21. 21••.
    Cheng S, Xing W, Pourteymoor S, Mohan S. Conditional disruption of the prolyl hydroxylase domain-containing protein 2 (Phd2) gene defines its key role in skeletal development. J Bone Miner Res. 2014;29:2276–86 Phd2 deletion in pre-osteoblasts decreases bone mass and microarchitecture, possibly through HIF-a-independent mechanisms that involve citamin C-induced osterix expression. CrossRefPubMedGoogle Scholar
  22. 22••.
    Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert SR, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117:1616–26 The first study to directly demonstrate genetic manipulation of oxygen-sensing in bone influences skeletal phenotype. CrossRefPubMedGoogle Scholar
  23. 23•.
    Shomento SH, Wan C, Cao X, Faugere M-C, Bouxsein ML, Clemens TL, et al. Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development. J Cell Biochem. 2010;109:196–204 Demonstration that HIF-1a and HIF-2a in mature osteoblasts have common and unique influence on bone microarchitecture and vascularization. CrossRefPubMedGoogle Scholar
  24. 24••.
    Stegen S, Stockmans I, Moermans K, Thienpont B, Maxwell PH, Carmeliet P, et al. Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin. Nat Comms. Nature Publishing Group; 2018;9:2557. Osteocytic oxygen-sensing exerts profound effects on bone via epistatic inhibition of Sost expression. Google Scholar
  25. 25••.
    Loots GG, Robling AG, Chang JC, Murugesh DK, Bajwa J, Carlisle C, et al. Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects. Bone. 2018;116:307–14 Using an osteocytic cre driver, osteocytic deletion of Vhl influences bone mass through Wnt-dependent and -independent mechanisms. CrossRefPubMedGoogle Scholar
  26. 26.
    Street J, Bao M, deGuzman L, Bunting S, Peale FV, Ferrara N, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA. 2002;99:9656–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Deckers MML, van Bezooijen RL, van der Horst G, Hoogendam J, Van Der Bent C, Papapoulos SE, et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology. 2002;143:1545–53.CrossRefPubMedGoogle Scholar
  28. 28.
    Ramasamy SK, Kusumbe AP, Wang L, Adams RH. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. Nature Publishing Group. 2014;507:376–80.Google Scholar
  29. 29.
    Maes C, Araldi E, Haigh K, Khatri R, Van Looveren R, Giaccia AJ, et al. VEGF-independent cellautonomous functions of HIF-1α regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J Bone Miner Res. Wiley-Blackwell. 2012;27:596–609.CrossRefGoogle Scholar
  30. 30.
    Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.CrossRefPubMedGoogle Scholar
  31. 31.
    Little R, Carulli J, Del Mastro R, Dupuis J, Osborne M, Folz C, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Armstrong VJ, Muzylak M, Sunters A, Zaman G, Saxon LK, Price JS, et al. Wnt/beta-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor alpha. J Biol Chem. 2007;282:20715–27.CrossRefPubMedGoogle Scholar
  33. 33.
    Tu X, Rhee Y, Condon K, Bivi N, Allen MR, Dwyer D, et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2011.Google Scholar
  34. 34.
    Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, et al. The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. 2006;281:23698–711.CrossRefPubMedGoogle Scholar
  35. 35.
    Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res. 2009;24:171–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Kato M, Patel M, Levasseur R, Lobov I, Chang B, Glass D, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157:303–14.CrossRefPubMedGoogle Scholar
  37. 37.
    Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286:19489–500.CrossRefPubMedGoogle Scholar
  38. 38.
    Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Research. 2005;15:928–35.CrossRefPubMedGoogle Scholar
  39. 39.
    Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43.CrossRefPubMedGoogle Scholar
  40. 40.
    Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68:577–89.CrossRefPubMedGoogle Scholar
  41. 41.
    Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39:91–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem. 2003;278:24113–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Nakanishi R, Shimizu M, Mori M, Akiyama H, Okudaira S, Otsuki B, et al. Secreted frizzled-related protein 4 is a negative regulator of peak BMD in SAMP6 mice. J Bone Miner Res. 2006;21:1713–21.CrossRefPubMedGoogle Scholar
  44. 44.
    Bodine PVN, Zhao W, Kharode YP, Bex FJ, Lambert A-J, Goad MB, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol. 2004;18:1222–37.CrossRefPubMedGoogle Scholar
  45. 45.
    Riddle RC, Leslie JM, Gross TS, Clemens TL. Hypoxia-inducible factor-1α protein negatively regulates load-induced bone formation. J Biol Chem. 2011;286:44449–56.CrossRefPubMedGoogle Scholar
  46. 46.
    Chen D, Li Y, Zhou Z, Xing Y, Zhong Y, Zou X, et al. Synergistic inhibition of Wnt pathway by HIF-1α and osteoblast-specific transcription factor osterix (Osx) in osteoblasts. Samant R, editor. PLoS ONE. Public Library of Science; 2012;7:e52948.Google Scholar
  47. 47.
    Genetos DC, Toupadakis CA, Raheja LF, Wong A, Papanicolaou SE, Fyhrie DP, et al. Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem. 2010;110:457–67.PubMedGoogle Scholar
  48. 48.
    Peng J, Lai ZG, Fang ZL, Xing S, Hui K, Hao C, et al. Dimethyloxalylglycine prevents bone loss in ovariectomized C57BL/6J mice through enhanced angiogenesis and osteogenesis. Samant R, editor. PLoS ONE. Public Library of Science; 2014;9:e112744.Google Scholar
  49. 49.
    Bouaziz W, Sigaux J, Modrowski D, Devignes C-S, Funck-Brentano T, Richette P, et al. Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. Proc Natl Acad Sci USA. National Academy of Sciences. 2016;113:5453–8.CrossRefGoogle Scholar
  50. 50.
    Javaheri B, Stern AR, Lara N, Dallas M, Zhao H, Liu Y, et al. Deletion of a single β-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Miner Res. 2014;29:705–15.CrossRefPubMedGoogle Scholar
  51. 51.
    Tu X, Delgado-Calle J, Condon KW, Maycas M, Zhang H, Carlesso N, et al. Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone. Proc Natl Acad Sci USA. National Acad Sciences; 2015 :201409857.Google Scholar
  52. 52.
    Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA. National Academy of Sciences; 2006;103:18154–9.Google Scholar
  53. 53.
    Lee DC, Sohn HA, Park Z-Y, Oh S, Kang YK, Lee K-M, et al. A lactate-induced response to hypoxia. Cell. 2015;161:595–609.CrossRefPubMedGoogle Scholar
  54. 54.
    Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R, et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009;15:682–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Melotte V, Qu X, Ongenaert M, van Criekinge W, de Bruine AP, Baldwin HS, et al. The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J. Federation of American Societies for Experimental Biology; 2010;24:4153–66.Google Scholar
  56. 56.
    Xing W, Pourteymoor S, Mohan S. Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway. Physiological Genomics. American Physiological Society Bethesda, MD; 2011;43:749–57.Google Scholar
  57. 57.
    Lahtinen T, Alhava EM, Karjalainen P, Romppanen T. The effect of age on blood flow in the proximal femur in man. Journal of Nuclear Medicine. 1981;22:966–72.PubMedGoogle Scholar
  58. 58.
    Burkhardt R, Kettner G, Bohm W, Schmidmeier M, Schlag R, Frisch B, et al. Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone. 1987;8:157–64.CrossRefPubMedGoogle Scholar
  59. 59.
    Prisby RD, Dominguez JM, Muller-Delp J, Allen MR, Delp MD. Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling. Malaval L, editor. PLoS ONE. Public Library of Science; 2012;7:e48564.Google Scholar
  60. 60.
    Senel K, Baykal T, Seferoglu B, Altas EU, Baygutalp F, Ugur M, et al. Circulating vascular endothelial growth factor concentrations in patients with postmenopausal osteoporosis. Arch Med Sci. Termedia. 2013;9:709–12.CrossRefGoogle Scholar
  61. 61.
    Zhao Q, Shen X, Zhang W, Zhu G, Qi J, Deng L. Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss. Bone. Elsevier Inc. 2012;50:763–70.Google Scholar
  62. 62.
    Komatsu D, Hadjiargyrou M. Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. Bone. 2004;34:680–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Toupadakis CA, Wong A, Genetos DC, Chung D-J, Murugesh D, Anderson MJ, et al. Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res. 2012.Google Scholar
  64. 64.
    Ward R. An update on disordered iron metabolism and iron overload. Hematology. 2010;15:311–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Wan C, Gilbert SR, Wang Y, Cao X, Shen X, Ramaswamy G, et al. Activation of the hypoxiainducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci USA. 2008;105:686–91.CrossRefPubMedGoogle Scholar
  66. 66.
    Donneys A, Deshpande SS, Tchanque-Fossuo CN, Johnson KL, Blough JT, Perosky JE, et al. Deferoxamine expedites consolidation during mandibular distraction osteogenesis. Bone. 2013;55:384–90.CrossRefPubMedGoogle Scholar
  67. 67.
    Shen X, Wan C, Ramaswamy G, Mavalli M, Wang Y, Duvall CL, et al. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res. 2009;27:1298–305.CrossRefPubMedGoogle Scholar
  68. 68.
    Stewart R, Goldstein J, Eberhardt A, Chu GT-MG, Gilbert S. Increasing vascularity to improve healing of a segmental defect of the rat femur. J Orthop Trauma. 2011;25:472–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Fan L, Li J, Yu Z, Dang X, Wang K. Hypoxia-inducible factor prolyl hydroxylase inhibitor prevents steroid-associated osteonecrosis of the femoral head in rabbits by promoting angiogenesis and inhibiting apoptosis. PLoS ONE. Public Library of Science; 2014;9:e107774. Pre-clinical evidence that small molecule PHD antagonists can mitigate avascular necrosis.Google Scholar
  70. 70•.
    Rankin EB, Wu C, Khatri R, Wilson TLS, Andersen R, Araldi E, et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012;149:63–74 Vhl deletion in osteoprogenitors causes a high bone mass and HIF-dependent polycythemia. CrossRefPubMedGoogle Scholar
  71. 71.
    Rabadi S, Udo I, Leaf DE, Waikar SS, Christov M. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol. 2018;314:F132–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Flamme I, Ellinghaus P, Urrego D, Kruger T. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. Jelkmann WEB, editor. PLoS ONE. Public Library of Science; 2017;12:e0186979.Google Scholar
  73. 73.
    Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, et al. Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica. Haematologica. 2017;102:e427–30.CrossRefPubMedGoogle Scholar
  74. 74.
    Zhang Q, Doucet M, Tomlinson RE, Han X, Quarles LD, Collins MT, et al. The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res. 2016;4:175–6.Google Scholar
  75. 75.
    Blau JE, Collins MT. The PTH-Vitamin D-FGF23 axis. Rev Endocr Metab Disord. Springer US. 2015;16:165–74.CrossRefGoogle Scholar
  76. 76.
    Johnson EO, Soultanis K, Soucacos PN. Vascular anatomy and microcirculation of skeletal zones vulnerable to osteonecrosis: vascularization of the femoral head. Orthop Clin North Am. 2004;35:285–91–viii.Google Scholar
  77. 77.
    Hong JM, Kim T-H, Chae S-C, Koo K-H, Lee YJ, Park EK, et al. Association study of hypoxia inducible factor 1alpha (HIF1alpha) with osteonecrosis of femoral head in a Korean population. Osteoarthr Cartil. 2007;15:688–94.CrossRefPubMedGoogle Scholar
  78. 78.
    Hong JM, Kim TH, Kim HJ, Park EK, Yang EK, Kim SY. Genetic association of angiogenesis- and hypoxia-related gene polymorphisms with osteonecrosis of the femoral head. Exp Mol Med. Nature Publishing Group. 2010;42:376–85.CrossRefGoogle Scholar
  79. 79.
    Radke S, Battmann A, Jatzke S, Eulert J, Jakob F, Schutze N. Expression of the angiomatrix and angiogenic proteins CYR61, CTGF, and VEGF in osteonecrosis of the femoral head. J Orthop Res. Wiley-Blackwell. 2006;24:945–52.CrossRefGoogle Scholar
  80. 80.
    Weinstein RS, Hogan EA, Borrelli MJ, Liachenko S, O'Brien CA, Manolagas SC. The Pathophysiological Sequence of Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Male Mice. Endocrinology. 2017;158:3817–31.CrossRefPubMedGoogle Scholar
  81. 81.
    Fowler TW, Acevedo C, Mazur CM, Hall-Glenn F, Fields AJ, Bale HA, et al. Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis. Sci Rep. 2017;7:44618.CrossRefPubMedGoogle Scholar
  82. 82.
    Wickham N, Crawford A, Carney AS, Goss AN. Bisphosphonate-associated osteonecrosis of the external auditory canal. J Laryngol Otol. Cambridge University Press; 2013;127 Suppl 2:S51–3.Google Scholar
  83. 83.
    McCadden L, Leonard CG, Primrose WJ. Bisphosphonate-induced osteonecrosis of the ear canal: our experience and a review of the literature. J Laryngol Otol. Cambridge University Press. 2018;132:372–4.CrossRefGoogle Scholar
  84. 84.
    Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res. 2003;9:2893–7.PubMedGoogle Scholar
  85. 85.
    Xiong H, Wei L, Hu Y, Zhang C, Peng B. Effect of alendronate on alveolar bone resorption and angiogenesis in rats with experimental periapical lesions. Int Endod J. Wiley/Blackwell (10.1111); 2010;43:485–91.Google Scholar
  86. 86.
    Soki FN, Li X, Berry J, Koh A, Sinder BP, Qian X, et al. The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches. J Cell Biochem. Wiley-Blackwell. 2013;114:67–78.CrossRefGoogle Scholar
  87. 87.
    Zhang L, Wang T, Chang M, Kaiser C, Kim JD, Wu T, et al. Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model. J Bone Miner Res. Wiley-Blackwell. 2017;32:1870–83.CrossRefGoogle Scholar
  88. 88.
    Jilka RL, O'Brien CA, Bartell SM, Weinstein RS, Manolagas SC. Continuous elevation of PTH increases the number of osteoblasts via both osteoclast-dependent and -independent mechanisms. J Bone Miner Res. Wiley-Blackwell. 2010;25:2427–37.CrossRefGoogle Scholar
  89. 89.
    Isowa S, Shimo T, Ibaragi S, Kurio N, Okui T, Matsubara K, et al. PTHrP regulates angiogenesis and bone resorption via VEGF expression. Anticancer Res. 2010;30:2755–67.PubMedGoogle Scholar
  90. 90.
    Prisby R, Guignandon A, Vanden-Bossche A, Mac-Way F, Linossier M-T, Thomas M, et al. Intermittent PTH(1-84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res. 2011;26:2583–96.CrossRefPubMedGoogle Scholar
  91. 91.
    Rhee Y, Park S-Y, Kim YM, Lee S, Lim SK. Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect. Biomed. Pharmacother. 2009;63:63–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Frey JL, Stonko DP, Faugere M-C, Riddle RC. Hypoxia-inducible factor-1α restricts the anabolic actions of parathyroid hormone. Bone Res. 2014;2:14005.CrossRefPubMedGoogle Scholar
  93. 93.
    Riddle RC, Clemens TL. Bone Cell Bioenergetics and Skeletal Energy Homeostasis. Physiological Reviews. 2017;97:667–98.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Anatomy, Physiology, and Cell Biology, School of Veterinary MedicineUniversity of California, DavisDavisUSA

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