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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 6

Deletion of Vhl in primary osteoblasts in vitro does not affect osteoblast proliferation and apoptosis.

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Deletion of Vhl in primary osteoblasts in vitro does not affect osteobla...
Confluent Vhl floxed primary osteoblast monolayers were infected with either adeno-GFP or adeno-CreM1 (100 MOI). Vhl mRNA expression in infected osteoblasts was determined by real-time PCR 48 hours after infection to assess deletion efficiency. Cell proliferation, apoptosis, and differentiation assays were performed as described in Methods. (A and B) Cell proliferation was assessed by flow cytometry using BrdU incorporation. (C and D) Cell apoptosis was assessed by flow cytometry using annexin V–PE staining. (E) Mineralized nodule formation was determined by ALP (left) and von Kossa staining (right) 7 and 14 days after cells were cultured in osteogenic medium. (F and G) Densitometric analysis of ALP and von Kossa staining observed in E using NIH ImageJ 1.36b. Data represent mean ± SEM. (H) Measurement of Vhl, Hif1a, runt-related transcription factor 2 (Runx2), and OC mRNA expression by quantitative real-time PCR at day 14 of osteogenic induction. **P < 0.01; ***P < 0.001.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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