Role of HIF-1alpha in skeletal development.
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.
Wan
Chao
C
Department of Orthopaedic Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. cwan@cuhk.edu.hk
Shao
Jin
J
Gilbert
Shawn R
SR
Riddle
Ryan C
RC
Long
Fanxin
F
Johnson
Randall S
RS
Schipani
Ernestina
E
Clemens
Thomas L
TL
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
D051795:Hypoxia-Inducible Factor 1, alpha Subunit
Nature. 1999 May 20;399(6733):271-5
10353251
Biochem Pharmacol. 2000 Jan 1;59(1):47-53
10605934
Cell. 2008 Feb 22;132(4):598-611
18295578
Blood. 1998 Oct 1;92(7):2260-8
9746763
Curr Top Dev Biol. 2005;65:169-87
15642383
Cell. 2007 Oct 19;131(2):324-36
17956733
J Bone Joint Surg Br. 1963 Aug;45:572-81
14058338
J Bone Joint Surg Br. 1961 Nov;43-B:800-13
14039826
Am J Physiol. 1952 Apr;169(1):26-33
14923858
J Biol Chem. 1997 Aug 1;272(31):19253-60
9235919
Mech Dev. 2002 Feb;111(1-2):61-73
11804779
Development. 2007 Nov;134(21):3917-28
17913788
EMBO J. 1998 Sep 1;17(17):5085-94
9724644
J Cell Biol. 2007 May 7;177(3):451-64
17470636
Proc Natl Acad Sci U S A. 1993 May 1;90(9):4304-8
8387214
J Biol Chem. 2001 Jan 19;276(3):2292-8
11056166
Mol Cell Biol. 2003 Jul;23(14):4959-71
12832481
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
9653127
Hypertension. 2002 Jan;39(1):46-50
11799077
Clin Sci (Lond). 2003 Oct;105(4):447-56
12780343
J Mol Med (Berl). 2009 Jun;87(6):583-90
19415227
Clin Orthop Relat Res. 1998 Oct;(355 Suppl):S7-21
9917622
J Clin Invest. 2007 Jun;117(6):1616-26
17549257
Science. 2001 Apr 20;292(5516):464-8
11292862
Development. 2002 Apr;129(8):1893-904
11934855
Blood. 1999 Sep 1;94(5):1561-7
10477681
Genes Dev. 2001 Nov 1;15(21):2865-76
11691837
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):686-91
18184809
Clin Orthop Relat Res. 1998 Oct;(355 Suppl):S82-9
9917629
Science. 2002 Feb 1;295(5556):807-8
11823627
Annu Rev Cell Dev Biol. 1999;15:551-78
10611972
Development. 2008 Feb;135(3):483-91
18094024
J Orthop Sci. 2004;9(4):410-4
15278782
Nat Med. 1999 Jun;5(6):623-8
10371499