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a Department of Pathology, University of Alabama at Birmingham, and the Veterans Administration Medical Center, Birmingham, Alabama, USA b Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
Key Words: HIF  • VHL • VEGF • angiogenesis • osteogenesis
Address for correspondence: Thomas L. Clemens, Ph.D., Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Volker Hall, G001, 1530 3rd Avenue S., Birmingham, AL 35294-0019. Voice: 205-934-2726; fax: 205-934-0043. tclemens{at}uab.edu
Osteogenesis and angiogenesis are tightly coupled during bone formation and repair. Blood vessels not only carry oxygen and nutrients to the developing bone, but also play an active role in bone formation and remodeling by mediating the interaction between osteoblasts, osteocytes, osteoclasts, and vascular cells at a variety of levels. Tissue hypoxia is believed to be a major stimulus for angiogenesis by activating hypoxia-inducible factor
(HIF) pathway, which is a central regulator of hypoxia adaptation in vertebrates. HIF remains inactive under normoxic conditions through pVHL-mediated polyubiquitination and proteasomal degradation. Activation of the HIF pathway by hypoxia triggers hypoxia-responsive gene expression, such as vascular endothelial growth factor (Vegf), which plays a critical role in angiogenesis, endochondral bone formation, and bone repair following fracture. Recent work from our laboratory has shown that osteoblasts use the HIF pathway to sense reduced oxygen tension and transmit signals that impinge on angiogenic and osteogenic gene programs during bone formation. Using a genetic approach, we have demonstrated that overexpression of HIF in mouse osteoblasts through disruption of Vhl results in profound increases in angiogenesis and osteogenesis, which appear to be mediated by cell nonautonomous mechanisms involving VEGF. These studies suggest that VEGF exerts many of its actions on bone indirectly by stimulation of angiogenesis. Whether or to what extent this angiogenic factor functions independent of endothelial cells remains to be determined.
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