Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 52, Pages 44449-44456Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.276683
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Funding
- National Institutes of Health [AR049410]
- Veterans Administration
- Johns Hopkins University Center for Musculoskeletal Research
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Mechanical loads induce profound anabolic effects in the skeleton, but the molecular mechanisms that transduce such signals are still poorly understood. In this study, we demonstrate that the hypoxia-inducible factor-1 alpha (Hif-1 alpha) is acutely up-regulated in response to exogenous mechanical stimuli secondary to prostanoid signaling and Akt/mTOR (mammalian target of rapamycin) activation. In this context, Hif-1 alpha associates with beta-catenin to inhibit Wnt target genes associated with bone anabolic activity. Mice lacking Hif-1 alpha in osteoblasts and osteocytes form more bone when subjected to tibia loading as a result of increased osteoblast activity. Taken together, these studies indicate that Hif-1 alpha serves as a negative regulator of skeletal mechanotransduction to suppress load-induced bone formation by altering the sensitivity of osteoblasts and osteocytes to mechanical signals.
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