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Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation

Title
Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation
Authors
Jang H.D.Shin J.H.Park D.R.Hong J.H.Yoon K.Ko R.Ko C.-Y.Kim H.-S.Jeong D.Kim N.Lee S.Y.
Ewha Authors
이수영
SCOPUS Author ID
이수영scopus
Issue Date
2011
Journal Title
Journal of Biological Chemistry
ISSN
0021-9258JCR Link
Citation
vol. 286, no. 45, pp. 39043 - 39050
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3β in osteoblasts is well characterized as a negative regulator of β-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3β inactivation upon receptor activator of NF-κB ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3β activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3β (GSK3β-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3β (GSK3β-K85R) or small interfering RNA (siRNA)-mediated GSK-3β silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3β further confirmed the negative role of GSK-3β in osteoclast formation. We also show that overexpression of the GSK3β-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca 2+ oscillations. Remarkably, transgenic mice expressing the GSK3β-S9A mutant show an osteopetrotic phenotype due to impaired osteoclast differentiation. Further, osteoclast precursor cells from the transgenic mice show defects in expression and nuclear localization of NFATc1. These findings demonstrate a novel role for GSK-3β in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI
10.1074/jbc.M111.256768
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자연과학대학 > 생명과학전공 > Journal papers
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