Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration.
The hypoxia-inducible factor-1alpha (HIF-1alpha) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1alpha pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1alpha activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1alpha in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1alpha pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.
Wan
Chao
C
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Gilbert
Shawn R
SR
Wang
Ying
Y
Cao
Xuemei
X
Shen
Xing
X
Ramaswamy
Girish
G
Jacobsen
Kimberly A
KA
Alaql
Zainab S
ZS
Eberhardt
Alan W
AW
Gerstenfeld
Louis C
LC
Einhorn
Thomas A
TA
Deng
Lianfu
L
Clemens
Thomas L
TL
D000818:Animals; D001696:Biomechanical Phenomena; D001861:Bone Regeneration / Q000502:physiology*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D040262:Receptors, Vascular Endothelial Growth Factor; C497446:VHL protein, human; C494469:VHL protein, mouse