title: GSK-3beta controls osteogenesis through regulating Runx2 activity.
abstract: Despite accumulated knowledge of various signalings regulating bone formation, the molecular network has not been clarified sufficiently to lead to clinical application. Here we show that heterozygous glycogen synthase kinase-3beta (GSK-3beta)-deficient mice displayed an increased bone formation due to an enhanced transcriptional activity of Runx2 by suppressing the inhibitory phosphorylation at a specific site. The cleidocranial dysplasia in heterozygous Runx2-deficient mice was significantly rescued by the genetic insufficiency of GSK-3beta or the oral administration of lithium chloride, a selective inhibitor of GSK-3beta. These results establish GSK-3beta as a key attenuator of Runx2 activity in bone formation and as a potential molecular target for clinical treatment of bone catabolic disorders like cleidocranial dysplasia.
authors.affiliation: Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kugimiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirata
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Chikuda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Azuma
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction