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Hypoxia-driven pathways in bone development, regeneration and disease

Abstract

Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischaemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions, including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxia-inducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have been used to identify important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor (VEGF)—a potent angiogenic factor and a downstream target of the HIF pathway—in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and blood, and pay particular attention to the complex relationship between HIF and VEGF in these tissues revealed by data from research using animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF.

Key Points

  • Oxygen levels regulate specific signalling cascades, such as the hypoxia-inducible factor (HIF) signalling pathway

  • HIFs are essential mediators of the complex homeostatic responses that enable hypoxic cells to survive and differentiate

  • Vascular endothelial growth factor (VEGF) is a downstream target of the HIF pathway and a potent angiogenic factor

  • HIFs and VEGF have critical roles in skeletal development and bone homeostasis, as well as in haematopoiesis

  • HIFs and VEGF are also crucial for bone regeneration and are involved in osteoarthritis and metastasis of tumours to bone

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Figure 1: The HIF-1α pathway.
Figure 2: The roles of HIF-1α and VEGF in regulating the oxygenation of cartilage during embryonic development.
Figure 3: The HIF and VEGF signalling pathway in bone.
Figure 4: Role of the HIF–VEGF–PlGF pathway in fracture repair.
Figure 5: Role of the HIF pathway in osteoarthritis.
Figure 6: Role of the HIF–VEGF–PIGF pathway in tumour metastasis to bone.

References

  1. 1

    Giaccia, A. J., Simon, M. C. & Johnson, R. The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev. 18, 2183–2194 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Dunwoodie, S. L. The role of hypoxia in development of the Mammalian embryo. Dev. Cell 17, 755–773 (2009).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Semenza, G. L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin. Cancer Biol. 19, 12–16 (2009).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Rankin, E. B. & Giaccia, A. J. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15, 678–685 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Bunn, H. F. & Poyton, R. O. Oxygen sensing and molecular adaptation to hypoxia. Physiol. Rev. 76, 839–885 (1996).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Giaccia, A., Siim, B. G. & Johnson, R. S. HIF-1 as a target for drug development. Nat. Rev. Drug Discov. 2, 803–811 (2003).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Kaelin, W. G. Jr. How oxygen makes its presence felt. Genes Dev. 16, 1441–1445 (2002).

    CAS  Google Scholar 

  9. 9

    Liu, L. & Simon, M. C. Regulation of transcription and translation by hypoxia. Cancer Biol. Ther. 3, 492–497 (2004).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Wenger, R. H. et al. The mouse gene for hypoxia-inducible factor-1α—genomic organization, expression and characterization of an alternative first exon and 5' flanking sequence. Eur. J. Biochem. 246, 155–165 (1997).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Pouysségur, J., Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006).

    PubMed  Article  CAS  Google Scholar 

  14. 14

    Chan, D. A., Suthphin, P. D., Denko, N. C. & Giaccia, A. J. Role of prolyl hydroxylation in oncogenically stabilized hyoxia-inducible factor-1α. J. Biol. Chem. 277, 40112–40117 (2002).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Min, J. H. et al. Structure of an HIF-1α–pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Wang, G. L. & Semenza, G. L. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl Acad. Sci. USA 90, 4304–4308 (1993).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Keith, B., Johnson, R. S. & Simon, M. C. HIF-1α and HIF2-α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20

    Zelzer, E. et al. Insulin induces transcription of target genes through the hypoxia-inducible factor 1α. EMBO J. 17, 5085–5094 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Araldi, E. & Schipani, E. Hypoxia, HIFs and bone development. Bone 47, 190–196 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Rankin, E. B., Giaccia, A. J. & Schipani, E. A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr. Osteoporos. Rep. 9, 46–52 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol. Cell. Biol. 23, 9361–9374 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Leo, C., Giaccia, A. J. & Denko, N. C. The hypoxic tumor microenvironment and gene expression. Semin. Radiat. Oncol. 14, 207–214 (2004).

    PubMed  Article  Google Scholar 

  26. 26

    Wykoff, C. C., Pugh, C. W., Maxwell, P. H., Harris, A. L. & Ratcliffe, P. J. Identification of novel hypoxia dependent and independent target genes of the von Hippel–Lindau (VHL) tumor suppressor by mRNA differential expression profiling. Oncogene 19, 6297–6305 (2000).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Greijer, A. E. et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J. Path. 206, 291–304 (2005).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Bishop, T. et al. Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. PLoS Biol. 2, e289 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29

    Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Zelzer, E. & Olsen, B. R. Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Curr. Top. Dev. Biol. 65, 169–187 (2005).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    CAS  Article  Google Scholar 

  34. 34

    Kronenberg, H. M. Developmental regulation of the growth plate. Nature 423, 332–336 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Provot, S. & Schipani, E. Molecular mechanisms of endochondral bone development. Biochem. Biophys. Res. Commun. 328, 658–665 (2005).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Schipani, E. et al. Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival. Genes Dev. 15, 2865–2876 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Maes, C. & Carmeliet, G. in VEGF in Development (ed. Ruhrberg, C.) 79–90 (Springer, Austin, 2008).

    Book  Google Scholar 

  38. 38

    Schipani, E., Maes, C., Carmeliet, G. & Semenza, G. L. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J. Bone Miner. Res. 24, 1347–1353 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Riddle, R. C., Khatri, R., Schipani, E. & Clemens, T. L. Role of hypoxia-inducible factor-1α in angiogenic-osteogenic coupling. J. Mol. Med. (Berl.) 87, 583–590 (2009).

    CAS  Article  Google Scholar 

  40. 40

    Hiraki, Y. & Shukunami, C. Angiogenesis inhibitors localized in hypovascular mesenchymal tissues: chondromodulin-I and tenomodulin. Connect. Tissue Res. 46, 3–11 (2005).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Maes, C. et al. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J. Clin. Invest. 113, 188–199 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Maes, C. et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell. 19, 329–344 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Maes, C. et al. VEGF-independent cell autonomous functions of HIF-1α in regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J. Bone Miner. Res. 27, 596–609 (2012).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Myllyharju, J. & Schipani, E. Extracellular matrix genes as hypoxia-inducible targets. Cell Tissue Res. 339, 19–29 (2010).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Pfander, D., Cramer, T., Schipani, E. & Johnson, R. S. HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes. J. Cell Sci. 116, 1819–1826 (2003).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Amarilio, R. et al. HIF-1α regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early chondrogenesis. Development 134, 3917–3928 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Provot, S. et al. HIF-1α regulates differentiation of limb bud mesenchyme and joint development. J. Cell Biol. 177, 451–464 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Robins, J. C. et al. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Bone 37, 313–322 (2005).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Lafont, J. E., Talma, S., Hopfgarten, C. & Murphy, C. L. Hypoxia promotes the differentiated human articular chondrocyte phenotype through SOX9-dependent and -independent pathways. J. Biol. Chem. 283, 4778–4786 (2008).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Goda, N. et al. Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol. Cell. Biol. 23, 359–369 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Araldi, E., Khatri, R., Giaccia, A. J., Simon, M. C. & Schipani, E. Lack of HIF-2α in limb bud mesenchyme causes a modest and transient delay of endochondral bone development. Nat. Med. 17, 25–29, (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Pfander, D. et al. Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development. Development 131, 2497–2508 (2004).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Zelzer, E. et al. VEGFA is necessary for chondrocyte survival during bone development. Development 131, 2161–2171 (2004).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Cramer, T., Schipani, E., Johnson, R. S., Swodoba, B. & Pfander, D. Expression of VEGF isoforms by epithelial chondrocytes during low-oxigen tension is HIF-1α dependent. Osteoarthritis Cartilage 12, 433–439 (2004).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Lin, C., McGough, R., Aswad, B., Block, J. A. & Terek, R. Hypoxia induces HIF-1α and VEGF expression in chondrosarcoma cells and chondrocytes. J. Orthop. Res. 22, 1175–1181 (2004).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5, 623–628 (1999).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Eshkar-Oren, I. et al. The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation of Vegf. Development 136, 1263–1272 (2009).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Karsenty, G. & Wagner, E. F. Reaching a genetic and molecular understanding of skeletal development. Dev. Cell 2, 389–406 (2002).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Takubo, K. et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Karsenty, G., Kronenberg, H. M. & Settembre, C. Genetic control of bone formation. Annu. Rev. Cell Dev. Biol. 25, 629–648 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Vu, T. H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–326 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Wang, Y. et al. The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development. J. Clin. Invest. 117, 1616–1626 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Shomento, S. H. et al. Hypoxia-inducible factors 1α and 2α exert both distinct and overlapping functions in long bone development. J. Cell. Biochem. 109, 196–204 (2010).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Maes, C. et al. Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO J. 29, 424–441 (2010).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Wu, J. Y., Scadden, D. T. & Kronenberg, H. M. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J. Bone Miner. Res. 24, 759–764 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Kiel, M. J. & Morrison, S. J. Uncertainty in the niches that maintain haematopoietic stem cells. Nat. Rev. Immunol. 8, 290–301 (2008).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    CAS  Article  Google Scholar 

  69. 69

    Brånemark, P.-I. Experimental investigation of microcirculation in bone marrow. Angiology 12, 293–305 (1961).

    Article  Google Scholar 

  70. 70

    Winkler, I. G. 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 116, 375–385 (2010).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Chow, D. C., Wenning, L. A., Miller, W. M. & Papoutsakis, E. T. Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys. J. 81, 685–696 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Xie, Y. et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Gerber, H. P. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Rehn, M. et al. Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. Blood 118, 1534–1543 (2011).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Gerstenfeld, L. C., Cullinane, D. M., Barnes, G. L., Graves, D. T. & Einhorn, T. A. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J. Cell. Biochem. 88, 873–884 (2003).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Street, J. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl Acad. Sci. USA 99, 9656–9661 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78

    Jacobsen, K. A. et al. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J. Bone Miner. Res. 23, 596–609 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).

    CAS  Article  Google Scholar 

  80. 80

    Schindeler, A., McDonald, M. M., Bokko, P. & Little, D. G. Bone remodeling during fracture repair: the cellular picture. Semin. Cell Dev. Biol. 19, 459–466 (2008).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Maes, C. et al. Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. J. Clin. Invest. 116, 1230–1242 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat. Rev. Cancer 8, 942–956 (2008).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Coenegrachts, L. et al. Anti-placental growth factor reduces bone metastasis by blocking tumor cell engraftment and osteoclast differentiation. Cancer Res. 70, 6537–6547 (2010).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Lohela, M., Bry, M., Tammela, T. & Alitalo, K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr. Opin. Cell Biol. 21, 154–165 (2009).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

    CAS  Article  Google Scholar 

  86. 86

    Wan, C. et al. Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration. Proc. Natl Acad. Sci. USA 105, 686–691 (2008).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Shen, X. et al. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J. Orthop. Res. 27, 1298–1305 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Pfander, D. & Gelse, K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr. Opin. Rheumatol. 19, 457–462 (2007).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Matsumoto, T. et al. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt1. Arthritis Rheum. 60, 1390–1405 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Yang, S. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–693 (2010).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nat. Med. 12, 895–904 (2006).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Bäuerle, T. et al. Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI. Neoplasia 10, 511–520 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94

    Hiraga, T., Kizaka-Kondoh, S., Hirota, K., Hiraoka, M. & Yoneda, T. Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Cancer Res. 67, 4157–4163 (2007).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Dunn, L. K. et al. Hypoxia and TGF-β drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PLoS ONE 4, e6896 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96

    Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Damato, S. et al. IDH1 mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas. Histopathology 60, 363–365 (2012).

    PubMed  Article  Google Scholar 

  98. 98

    Vissers, L. E. et al. Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D2hydroxyglutaric aciduria (MC-HGA). Am. J. Med. Genet. A 155A, 2609–2616 (2011).

    PubMed  Article  CAS  Google Scholar 

  99. 99

    Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The authors' research is supported by NIH grants RO1 AR04819106 to E. Schipani; FWO G.0569.07, G.0500.08 and G.0982.11 to G. Carmeliet; and Grant 282131 from the European Research Council under the European Union's Seventh Framework Programme (FP7/20072013) to C. Maes.

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Correspondence to Ernestina Schipani.

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Maes, C., Carmeliet, G. & Schipani, E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol 8, 358–366 (2012). https://doi.org/10.1038/nrrheum.2012.36

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