The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development

Jun 6, 2007The Journal of clinical investigation

How low-oxygen signaling links new blood vessel growth to bone formation during skeleton development

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Abstract

Mice overexpressing HIF alpha in osteoblasts developed extremely dense, heavily vascularized long bones.

HIF alpha promotes blood vessel formation and bone growth by increasing VEGF levels in osteoblasts.
Selective deletion of the von Hippel-Lindau gene in osteoblasts results in high Vegf expression.
Mice without Hif1a in osteoblasts displayed thinner, less vascularized long bones compared to controls.
Loss of von Hippel-Lindau in osteoblasts enhanced blood vessel sprouting from embryonic metatarsals in laboratory settings.
Mice lacking both von Hippel-Lindau and Hif1a exhibited a bone phenotype that was intermediate between the two single mutants.

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Skeletal development and turnover occur in close spatial and temporal association with angiogenesis. Osteoblasts are ideally situated in bone to sense oxygen tension and respond to hypoxia by activating the hypoxia-inducible factor alpha (HIF alpha) pathway. Here we provide evidence that HIF alpha promotes angiogenesis and osteogenesis by elevating VEGF levels in osteoblasts. Mice overexpressing HIF alpha in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones. By contrast, mice lacking Hif1a in osteoblasts had the reverse skeletal phenotype of that of the Vhl mutants: long bones were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Mice lacking both Vhl and Hif1a had a bone phenotype intermediate between those of the single mutants, suggesting overlapping functions of HIFs in bone. These studies suggest that activation of the HIF alpha pathway in developing bone increases bone modeling events through cell-nonautonomous mechanisms to coordinate the timing, direction, and degree of new blood vessel formation in bone.

The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development

Abstract

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