Current Osteoporosis Reports

, Volume 9, Issue 2, pp 46–52 | Cite as

A Central Role for Hypoxic Signaling in Cartilage, Bone, and Hematopoiesis

  • Erinn B. Rankin
  • Amato J. Giaccia
  • Ernestina Schipani


Hypoxic signaling plays an essential role in maintaining oxygen homeostasis and cell survival. Hypoxia-inducible transcription factors HIF-1 and HIF-2 are central mediators of the cellular response to hypoxia by regulating the expression of genes controlling metabolic adaptation, oxygen delivery, and survival in response to oxygen deprivation. Recent studies have identified an important role for HIF-1 and HIF-2 in the regulation of skeletal development, bone formation, and regeneration, as well as joint formation and homeostasis. In addition, overexpression of HIF-1 and HIF-2 is clinically associated with osteosarcoma and osteoarthritis. Together, these findings implicate hypoxic signaling as a central regulator of bone biology and disease.


Hypoxia Bone VHL HIF-1 HIF-2 Cartilage Hematopoiesis Osteoarthritis Osteosarcoma Osteogenesis Angiogenesis Osteoblast Chondrocyte Limb bud mesenchyme Joint 



This paper was supported by National Institutes of Health RO1 AR048191-06 to E. Schipani.


No potential conflicts of interest relevant to this article were reported.


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

  1. 1.
    Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Ivan M, Haberberger T, Gervasi DC, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA. 2002;99:13459–64.PubMedCrossRefGoogle Scholar
  3. 3.
    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;292:468–72.PubMedCrossRefGoogle Scholar
  4. 4.
    Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Pan Y, Mansfield KD, Bertozzi CC, et al. Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell Biol. 2007;27:912–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Hu CJ, Iyer S, Sataur A, et al. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol. 2006;26:3514–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Mole DR, Blancher C, Copley RR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284:16767–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15:2675–86.PubMedCrossRefGoogle Scholar
  11. 11.
    Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466–71.PubMedCrossRefGoogle Scholar
  12. 12.
    Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol. 2006;76:217–57.PubMedCrossRefGoogle Scholar
  13. 13.
    Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17:3005–15.PubMedCrossRefGoogle Scholar
  14. 14.
    Maltepe E, Schmidt JV, Baunoch D, et al. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature. 1997;386:403–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kozak KR, Abbott B, Hankinson O. ARNT-deficient mice and placental differentiation. Dev Biol. 1997;191:297–305.PubMedCrossRefGoogle Scholar
  16. 16.
    Tian H, Hammer RE, Matsumoto AM, et al. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 1998;12:3320–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Peng J, Zhang L, Drysdale L, et al. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci USA. 2000;97:8386–91.PubMedCrossRefGoogle Scholar
  18. 18.
    Compernolle V, Brusselmans K, Acker T, et al. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med. 2002;8:702–10.PubMedGoogle Scholar
  19. 19.
    Scortegagna M, Ding K, Oktay Y, et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat Genet. 2003;35:331–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Schipani E, Ryan HE, Didrickson S, et al. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev. 2001;15:2865–76.PubMedGoogle Scholar
  21. 21.
    Amarilio R, Viukov SV, Sharir A, et al. HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development. 2007;134:3917–28.PubMedCrossRefGoogle Scholar
  22. 22.
    Provot S, Zinyk D, Gunes Y, et al. Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development. J Cell Biol. 2007;177:451–64.PubMedCrossRefGoogle Scholar
  23. 23.
    Araldi E, Schipani E. Hypoxia, HIFs and bone development. Bone. 2010;47:190–6.PubMedCrossRefGoogle Scholar
  24. 24.
    • Saito T, Fukai A, Mabuchi A, et al.: Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 2010, 16:678–686. This paper demonstrates that HIF-2 contributes to osteoarthritis in mice and humans.PubMedCrossRefGoogle Scholar
  25. 25.
    • Araldi E, Khatri R, Giaccia AJ, et al.: Lack of hypoxia-inducible factor-2a in limb bud mesenchyme causes a modest and transient delay of endochondral bone development. Nat Med 2011, 17:1–2. This paper demonstrates that loss of HIF-2 in the limb bud mesenchyme results in only a mild and transient delay in endochondral bone development.CrossRefGoogle Scholar
  26. 26.
    Pfander D, Kobayashi T, Knight MC, et al. Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development. Development. 2004;131:2497–508.PubMedCrossRefGoogle Scholar
  27. 27.
    Gruber M, Hu CJ, Johnson RS, et al. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci USA. 2007;104:2301–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Mack FA, Rathmell WK, Arsham AM, et al. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell. 2003;3:75–88.PubMedCrossRefGoogle Scholar
  29. 29.
    Welford SM, Dorie MJ, Li X, et al. Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol Cell Biol. 2010;30:4595–603.PubMedCrossRefGoogle Scholar
  30. 30.
    Vu TH, Shipley JM, Bergers G, et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998;93:411–22.PubMedCrossRefGoogle Scholar
  31. 31.
    • Maes C, Kobayashi T, Selig MK, et al.: Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell 2010, 19:329–344. This paper genetically followed the fate of cells of the osteoblastic lineage and found that osterix-expressing osteoprogenitor cells give rise to trabecular bone, osteocytes, and stromal cells inside the developing bone.PubMedCrossRefGoogle Scholar
  32. 32.
    • 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. This paper genetically demonstrates that the hypoxia signaling pathway couples osteogenesis to angiogenesis in vivo.PubMedCrossRefGoogle Scholar
  33. 33.
    Shomento SH, Wan C, Cao X, 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.PubMedGoogle Scholar
  34. 34.
    Wan C, Gilbert SR, Wang Y, et al. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci USA. 2008;105:686–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Maes C, Carmeliet P, Moermans K, et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002;111:61–73.PubMedCrossRefGoogle Scholar
  36. 36.
    Zelzer E, McLean W, Ng YS, et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development. 2002;129:1893–904.PubMedGoogle Scholar
  37. 37.
    Gerber HP, Vu TH, Ryan AM, et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5:623–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Zelzer E, Mamluk R, Ferrara N, et al. VEGFA is necessary for chondrocyte survival during bone development. Development. 2004;131:2161–71.PubMedCrossRefGoogle Scholar
  39. 39.
    Zelzer E, Olsen B. Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth and repair. Curr Top Dev Biol. 2005;65:169–87.PubMedCrossRefGoogle Scholar
  40. 40.
    Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010;7:150–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Jungermann K, Kietzmann T. Role of oxygen in the zonation of carbohydrate metabolism and gene expression in liver. Kidney Int. 1997;51:402–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Winkler IG, Barbier V, Wadley R, et al. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood. 2010;116:375–85.PubMedCrossRefGoogle Scholar
  43. 43.
    Branemark PI. Experimental investigation of microcirculation in bone marrow. Angiology. 1961;12:293–305.CrossRefGoogle Scholar
  44. 44.
    Chow DC, Wenning LA, Miller WM, et al. Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J. 2001;81:685–96.PubMedCrossRefGoogle Scholar
  45. 45.
    Wan C, Shao J, Gilbert SR, et al. Role of HIF-1alpha in skeletal development. Ann NY Acad Sci. 2010;1192:322–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Komatsu DE, Bosch-Marce M, Semenza GL, et al. Enhanced bone regeneration associated with decreased apoptosis in mice with partial HIF-1alpha deficiency. J Bone Miner Res. 2007;22:366–74.PubMedCrossRefGoogle Scholar
  47. 47.
    Bozec A, Bakiri L, Hoebertz A, et al. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature. 2008;454:221–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Knowles HJ, Athanasou NA. Acute hypoxia and osteoclast activity: a balance between enhanced resorption and increased apoptosis. J Pathol. 2009;218:256–64.PubMedCrossRefGoogle Scholar
  49. 49.
    Gerstenfeld LC, Cullinane DM, Barnes GL, et al. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003;88:873–84.PubMedCrossRefGoogle Scholar
  50. 50.
    Shen X, Wan C, Ramaswamy G, et al. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res. 2009;27:1298–305.PubMedCrossRefGoogle Scholar
  51. 51.
    Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89:765–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64.PubMedCrossRefGoogle Scholar
  53. 53.
    Wu JY, Scadden DT, Kronenberg HM. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J Bone Miner Res. 2009;24:759–64.PubMedCrossRefGoogle Scholar
  54. 54.
    Mendez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–41.PubMedCrossRefGoogle Scholar
  57. 57.
    • Chan CK, Chen CC, Luppen CA, et al.: Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 2009, 457:490–494. This study demonstrates that osterix-expressing osteoprogenitor cells are required for ectopic HSC niche formation.PubMedCrossRefGoogle Scholar
  58. 58.
    Xie Y, Yin T, Wiegraebe W, et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457:97–101.PubMedCrossRefGoogle Scholar
  59. 59.
    Parmar K, Mauch P, Vergilio JA, et al. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA. 2007;104:5431–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Danet GH, Pan Y, Luongo JL, et al. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest. 2003;112:126–35.PubMedGoogle Scholar
  61. 61.
    Hermitte F. Brunet de la Grange P, Belloc F, et al.: Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells. 2006;24:65–73.PubMedCrossRefGoogle Scholar
  62. 62.
    • Simsek T, Kocabas F, Zheng J, et al.: The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 2010, 7:380–390. This study demonstrates that HSCs are hypoxic in vivo and HIF signaling drives glycolysis rather than mitochondrial respiration for the generation of adenosine 5′-triphosphate in these cells.PubMedCrossRefGoogle Scholar
  63. 63.
    • Takubo K, Goda N, Yamada W, et al.: Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 2010, 7:391–402. Using genetic mouse models, this study demonstrates that HIF-1 levels are important in regulating HSC function in vivo.PubMedCrossRefGoogle Scholar
  64. 64.
    Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317–20.PubMedCrossRefGoogle Scholar
  65. 65.
    Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361:2059–67.PubMedCrossRefGoogle Scholar
  66. 66.
    Sprenger SH, Gijtenbeek JM, Wesseling P, et al. Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization. J Neurooncol. 2001;52:241–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.PubMedCrossRefGoogle Scholar
  68. 68.
    Chau NM, Rogers P, Aherne W, et al. Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res. 2005;65:4918–28.PubMedCrossRefGoogle Scholar
  69. 69.
    Yang QC, Zeng BF, Dong Y, et al. Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome. Jpn J Clin Oncol. 2007;37:127–34.PubMedCrossRefGoogle Scholar
  70. 70.
    Mizobuchi H, Garcia-Castellano JM, Philip S, et al. Hypoxia markers in human osteosarcoma: an exploratory study. Clin Orthop Relat Res. 2008;466:2052–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Knowles HJ, Schaefer KL, Dirksen U, et al. Hypoxia and hypoglycaemia in Ewing’s sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor. BMC Cancer. 2010;10:372.PubMedCrossRefGoogle Scholar
  72. 72.
    Yang S, Kim J, Ryu JH, et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med. 2010;16:687–93.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Erinn B. Rankin
    • 1
    • 2
  • Amato J. Giaccia
    • 2
  • Ernestina Schipani
    • 1
  1. 1.Endocrine Unit, Massachusetts General Hospital-Harvard Medical SchoolBostonUSA
  2. 2.Division of Radiation and Cancer Biology, Department of Radiation OncologyStanford UniversityStanfordUSA

Personalised recommendations