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Current Osteoporosis Reports

Erschienen in:

01.06.2011

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

verfasst von: Erinn B. Rankin, Amato J. Giaccia, Ernestina Schipani

Erschienen in: Current Osteoporosis Reports | Ausgabe 2/2011

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Abstract

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.

Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678–85.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

12.

Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol. 2006;76:217–57.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

15.

Kozak KR, Abbott B, Hankinson O. ARNT-deficient mice and placental differentiation. Dev Biol. 1997;191:297–305.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

23.

Araldi E, Schipani E. Hypoxia, HIFs and bone development. Bone. 2010;47:190–6.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

38.

Zelzer E, Mamluk R, Ferrara N, et al. VEGFA is necessary for chondrocyte survival during bone development. Development. 2004;131:2161–71.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

43.

Branemark PI. Experimental investigation of microcirculation in bone marrow. Angiology. 1961;12:293–305.CrossRef

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.PubMedCrossRef

45.

Wan C, Shao J, Gilbert SR, et al. Role of HIF-1alpha in skeletal development. Ann NY Acad Sci. 2010;1192:322–6.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

48.

Knowles HJ, Athanasou NA. Acute hypoxia and osteoclast activity: a balance between enhanced resorption and increased apoptosis. J Pathol. 2009;218:256–64.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

55.

Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

64.

Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317–20.PubMedCrossRef

65.

Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361:2059–67.PubMedCrossRef

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.PubMedCrossRef

67.

Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

Titel: A Central Role for Hypoxic Signaling in Cartilage, Bone, and Hematopoiesis
verfasst von: Erinn B. Rankin
Amato J. Giaccia
Ernestina Schipani
Publikationsdatum: 01.06.2011
Verlag: Current Science Inc.
Erschienen in: Current Osteoporosis Reports / Ausgabe 2/2011
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-011-0047-2

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

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