title: Role of HIF-1alpha in skeletal development.
abstract: Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. Mesenchymal cells in the developing stroma elicit angiogenic signals to recruit new blood vessels into bone. Reciprocal signals, likely emanating from the incoming vascular endothelium, stimulate mesenchymal cell specification through additional interactions with cells within the vascular stem cell niche. The hypoxia-inducible factor-1 alpha (HIF-1) pathway has been identified as a key component in this process. We demonstrated that overexpression of HIF-1 in mature osteoblasts through disruption of the von Hippel-Lindau protein profoundly increases angiogenesis and osteogenesis; these processes appear to be coupled by cell nonautonomous mechanisms involving the action of vascular endothelial growth factor (VEGF) on the endothelial cells. The same occurred in the model of injury-mediated bone regeneration (distraction osteogenesis). Surprisingly, manipulation of HIF-1 does not influence angiogenesis of the skull bones, where earlier activation of HIF-1 in the condensing mesenchyme upregulates osterix during cranial bone formation.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. cwan@cuhk.edu.hk
authors.forename: Chao
authors.initials: C
authors.lastname: Wan
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Gilbert
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Riddle
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000196:embryology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012886:Skull / Q000196:embryology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
references.citation: Nature. 1999 May 20;399(6733):271-5
references.pmid: 10353251
references.citation: Biochem Pharmacol. 2000 Jan 1;59(1):47-53
references.pmid: 10605934
references.citation: Cell. 2008 Feb 22;132(4):598-611
references.pmid: 18295578
references.citation: Blood. 1998 Oct 1;92(7):2260-8
references.pmid: 9746763
references.citation: Curr Top Dev Biol. 2005;65:169-87
references.pmid: 15642383
references.citation: Cell. 2007 Oct 19;131(2):324-36
references.pmid: 17956733
references.citation: J Bone Joint Surg Br. 1963 Aug;45:572-81
references.pmid: 14058338
references.citation: J Bone Joint Surg Br. 1961 Nov;43-B:800-13
references.pmid: 14039826
references.citation: Am J Physiol. 1952 Apr;169(1):26-33
references.pmid: 14923858
references.citation: J Biol Chem. 1997 Aug 1;272(31):19253-60
references.pmid: 9235919
references.citation: Mech Dev. 2002 Feb;111(1-2):61-73
references.pmid: 11804779
references.citation: Development. 2007 Nov;134(21):3917-28
references.pmid: 17913788
references.citation: EMBO J. 1998 Sep 1;17(17):5085-94
references.pmid: 9724644
references.citation: J Cell Biol. 2007 May 7;177(3):451-64
references.pmid: 17470636
references.citation: Proc Natl Acad Sci U S A. 1993 May 1;90(9):4304-8
references.pmid: 8387214
references.citation: J Biol Chem. 2001 Jan 19;276(3):2292-8
references.pmid: 11056166
references.citation: Mol Cell Biol. 2003 Jul;23(14):4959-71
references.pmid: 12832481
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
references.pmid: 9653127
references.citation: Hypertension. 2002 Jan;39(1):46-50
references.pmid: 11799077
references.citation: Clin Sci (Lond). 2003 Oct;105(4):447-56
references.pmid: 12780343
references.citation: J Mol Med (Berl). 2009 Jun;87(6):583-90
references.pmid: 19415227
references.citation: Clin Orthop Relat Res. 1998 Oct;(355 Suppl):S7-21
references.pmid: 9917622
references.citation: J Clin Invest. 2007 Jun;117(6):1616-26
references.pmid: 17549257
references.citation: Science. 2001 Apr 20;292(5516):464-8
references.pmid: 11292862
references.citation: Development. 2002 Apr;129(8):1893-904
references.pmid: 11934855
references.citation: Blood. 1999 Sep 1;94(5):1561-7
references.pmid: 10477681
references.citation: Genes Dev. 2001 Nov 1;15(21):2865-76
references.pmid: 11691837
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):686-91
references.pmid: 18184809
references.citation: Clin Orthop Relat Res. 1998 Oct;(355 Suppl):S82-9
references.pmid: 9917629
references.citation: Science. 2002 Feb 1;295(5556):807-8
references.pmid: 11823627
references.citation: Annu Rev Cell Dev Biol. 1999;15:551-78
references.pmid: 10611972
references.citation: Development. 2008 Feb;135(3):483-91
references.pmid: 18094024
references.citation: J Orthop Sci. 2004;9(4):410-4
references.pmid: 15278782
references.citation: Nat Med. 1999 Jun;5(6):623-8
references.pmid: 10371499