title: Hypoxia-inducible factor-1α protein negatively regulates load-induced bone formation.
abstract: 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-1α (Hif-1α) 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-1α associates with β-catenin to inhibit Wnt target genes associated with bone anabolic activity. Mice lacking Hif-1α 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-1α 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.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Riddle
authors.forename: Julie M
authors.initials: JM
authors.lastname: Leslie
authors.forename: Ted S
authors.initials: TS
authors.lastname: Gross
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
mesh_terms: D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051153:Wnt Proteins; D051176:beta Catenin; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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