Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration

被引:458
作者
Wan, Chao [1 ]
Gilbert, Shawn R. [2 ]
Wang, Ying [1 ]
Cao, Xuemei [1 ]
Shen, Xing [1 ]
Ramaswamy, Girish [3 ]
Jacobsen, Kimberly A. [4 ]
Alaql, Zainab S. [4 ]
Eberhardt, Alan W. [3 ]
Gerstenfeld, Louis C. [4 ]
Einhorn, Thomas A.
Deng, Lianfu [1 ]
Clemens, Thomas L. [1 ,5 ]
机构
[1] Univ Alabama Birmingham, Dept Pathol, Div Mol & Cellular Pathol, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA
[4] Boston Univ, Med Ctr, Dept Orthopaed Surg, Boston, MA 02118 USA
[5] Vet Adm Med Ctr, Birmingham, AL 35294 USA
关键词
von Hippel-Lindau protein; VEGF; angiogenesis; distraction osteogenesis;
D O I
10.1073/pnas.0708474105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 [理学]; 0710 [生物学]; 09 [农学];
摘要
The hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1 alpha 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-1 alpha pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.
引用
收藏
页码:686 / 691
页数:6
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