The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development
Ying Wang, Chao Wan, Lianfu Deng, Ximeng Liu, Xuemei Cao, Shawn R. Gilbert, Mary L. Bouxsein, Marie-Claude Faugere, Robert E. Guldberg, Louis C. Gerstenfeld, Volker H. Haase, Randall S. Johnson, Ernestina Schipani, Thomas L. Clemens
Ying Wang, Chao Wan, Lianfu Deng, Ximeng Liu, Xuemei Cao, Shawn R. Gilbert, Mary L. Bouxsein, Marie-Claude Faugere, Robert E. Guldberg, Louis C. Gerstenfeld, Volker H. Haase, Randall S. Johnson, Ernestina Schipani, Thomas L. Clemens
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Research Article

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

Abstract

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 α (HIFα) pathway. Here we provide evidence that HIFα promotes angiogenesis and osteogenesis by elevating VEGF levels in osteoblasts. Mice overexpressing HIFα 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 HIFα 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.

Authors

Ying Wang, Chao Wan, Lianfu Deng, Ximeng Liu, Xuemei Cao, Shawn R. Gilbert, Mary L. Bouxsein, Marie-Claude Faugere, Robert E. Guldberg, Louis C. Gerstenfeld, Volker H. Haase, Randall S. Johnson, Ernestina Schipani, Thomas L. Clemens

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Figure 3

Disruption of Vhl in osteoblasts increases long bone volume.

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Disruption of Vhl in osteoblasts increases long bone volume. ...
(A) Representative μCT images of the femurs from ΔVhl and control mice at the age of 3, 6, and 12 weeks. Scale bars: 5.0 mm. (B) Representative femoral cross sections from 6-week-old ΔVhl and control mice. Scale bars: 1.0 mm. (C–E) Histomorphometric analyses were performed on femoral sections from ΔVhl mice and controls at 3 weeks of age as described in Methods. Comparisons of trabecular bone volume (C), trabecular separation (D), and bone formation rate per osteoblast (E) in control (white bars; n = 6) and ΔVhl mice (black bars; n = 7) are shown. Data represent mean ± SEM. *P < 0.05; **P < 0.01. (F) Seven-day-old mice were labeled with sequential doses of calcein before sacrifice. Representative calcein-labeled sections of distal femur from control and ΔVhl mice are shown. Original magnification, ×400. (G) Quantitative histomorphometric measurement of osteoblast number was performed at the distal femur of 7-day-old ΔVhl (black bar; n = 3) and control mice (white bar; n = 3). Data represent mean ± SEM. *P < 0.05.