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The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development
Ying Wang, … , Ernestina Schipani, Thomas L. Clemens
Ying Wang, … , Ernestina Schipani, Thomas L. Clemens
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1616-1626. https://doi.org/10.1172/JCI31581.
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Research Article

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

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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 2

Osteoblast-specific, Cre-mediated deletion of Vhl.

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Osteoblast-specific, Cre-mediated deletion of Vhl.
               
(A) P...
(A) PCR analysis of Cre-mediated recombination in selected tissues from a ΔVhl mouse. The recombined allele (Δflox) was present exclusively in bone tissue. (B) Representative histological sections of distal femurs from 6-week-old control and ΔVhl mice after staining with antibodies against pVHL (left), HIF-1α (middle), or HIF-2α (right) as described in Methods. Sections were counterstained with hematoxylin. Red arrows indicate positive staining and black arrows negative staining in osteoblasts. Original magnification, ×400. (C and D) Confluent monolayers of Vhl floxed primary osteoblasts were infected with either Ad-GFP or Ad-CreM1 (100 MOI) for 48 hours. (C) Proteins in the cytoplasm and nucleus were extracted separately and analyzed by immunoblotting with antibodies against pVHL, HIF-1α, and HIF-2α. Immunoblots for TBP and α-tubulin were used as loading controls for nuclear and cytoplasmic proteins, respectively. TBP, TATA box–binding protein. (D) Total mRNA was extracted from confluent monolayers of osteoblasts 48 hours after adenoviral infection, and gene expression for Vhl, Vegf, and Glut1 was determined by quantitative real-time PCR. White bars represent Ad-GFP infection; black bars represent Ad-CreM1 infection. *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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