title: Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development.
abstract: The hypoxia-inducible factors have recently been identified as critical regulators of angiogenic-osteogenic coupling. Mice overexpressing HIFalpha subunits in osteoblasts produce abundant VEGF and develop extremely dense, highly vascularized long bones. In this study, we investigated the individual contributions of Hif-1alpha and Hif-2alpha in angiogenesis and osteogenesis by individually disrupting each Hifalpha gene in osteoblasts using the Cre-loxP method. Mice lacking Hif-1alpha demonstrated markedly decreased trabecular bone volume, reduced bone formation rate, and altered cortical bone architecture. By contrast, mice lacking Hif-2alpha had only a modest decrease in trabecular bone volume. Interestingly, long bone blood vessel development measured by angiography was decreased by a similar degree in both DeltaHif-1alpha and DeltaHif-2alpha mice suggesting a common role for these Hifalpha subunits in skeletal angiogenesis. In agreement with this idea, osteoblasts lacking either Hif-1alpha or Hif-2alpha had profound reductions in VEGF mRNA expression but only the loss of Hif-1alpha impaired osteoblast proliferation. These findings indicate that expression of both Hif-1alpha and Hif-2alpha by osteoblasts is required for long bone development. We propose that both Hif-1alpha and Hif-2alpha function through cell non-autonomous modes to promote vascularization of bone and that Hif-1alpha also promotes bone formation by exerting direct actions on the osteoblast.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Stacy H
authors.initials: SH
authors.lastname: Shomento
authors.forename: Chao
authors.initials: C
authors.lastname: Wan
authors.forename: Xuemei
authors.initials: X
authors.lastname: Cao
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Faugere
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Riddle
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001846:Bone Development / Q000502:physiology*; D001842:Bone and Bones / Q000098:blood supply / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse