GSK-3beta controls osteogenesis through regulating Runx2 activity.
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.
Kugimiya
Fumitaka
F
Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan.
Kawaguchi
Hiroshi
H
Ohba
Shinsuke
S
Kawamura
Naohiro
N
Hirata
Makoto
M
Chikuda
Hirotaka
H
Azuma
Yoshiaki
Y
Woodgett
James R
JR
Nakamura
Kozo
K
Chung
Ung-il
UI
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