GSK-3β 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-3β (GSK-3β)-deficient mice displayed an increased bone formation due to an...

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Bibliographic Details
Published inPloS one Vol. 2; no. 9; p. e837
Main Authors Kugimiya, Fumitaka, Kawaguchi, Hiroshi, Ohba, Shinsuke, Kawamura, Naohiro, Hirata, Makoto, Chikuda, Hirotaka, Azuma, Yoshiaki, Woodgett, James R, Nakamura, Kozo, Chung, Ung-il
Format Journal Article
LanguageEnglish
Published San Francisco Public Library of Science 05.09.2007
Subjects
Biocompatibility
Biology
Bone density
Bone dysplasia
Bone growth
Bone marrow
Cbfa-1 protein
Cell Biology/Developmental Molecular Mechanisms
Craniofacial syndromes
Developmental Biology/Cell Differentiation
Diabetes
Fibroblasts
Gene expression
Genetics and Genomics/Animal Genetics
Glycogen
Glycogen synthase kinase 3
Growth factors
Insulin
Integrative medicine
Kinases
Lithium
Lithium chloride
Medicine
Metabolism
Mice
Musculoskeletal system
Oral administration
Osteogenesis
Osteoporosis
Phosphorylation
Proteins
Studies
Transcription
Transcription factors
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Summary: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-3β (GSK-3β)-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-3β or the oral administration of lithium chloride, a selective inhibitor of GSK-3β. These results establish GSK-3β 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.
Bibliography:Conceived and designed the experiments: HK FK UC. Performed the experiments: NK FK SO MH. Analyzed the data: FK KN. Contributed reagents/materials/analysis tools: JW NK SO HC YA. Wrote the paper: FK.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0000837