Inactivation of Glycogen Synthase Kinase-3 beta Is Required for Osteoclast Differentiation

Title
Inactivation of Glycogen Synthase Kinase-3 beta Is Required for Osteoclast Differentiation
Author(s)
정대원장현덕[장현덕]신지혜[신지혜]박두리[박두리]홍진희[홍진희]윤기염[윤기염]고려진[고려진]고창용[고창용]김한성[김한성]김낙성[김낙성]이수영[이수영]
Keywords
KAPPA-B ACTIVATION; BONE HOMEOSTASIS; RANKL; GSK3; EXPRESSION; NFATC1; KINASE; MICE; PHOSPHORYLATION; CALCINEURIN
Issue Date
201111
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.286, no.45, pp.39043 - 39050
Abstract
Glycogen synthase kinase-3 beta (GSK-3 beta is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3 beta in osteoblasts is well characterized as a negative regulator of beta-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3 beta inactivation upon receptor activator of NF-kappa B ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3 beta activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3 beta (GSK3 beta-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3 beta (GSK3 beta-K85R) or small interfering RNA (siRNA)-mediated GSK-3 beta silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3 beta further confirmed the negative role of GSK-3 beta in osteoclast formation. We also show that overexpression of the GSK3 beta-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3 beta-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-3 beta in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling.
URI
http://hdl.handle.net/YU.REPOSITORY/24262http://dx.doi.org/10.1074/jbc.M111.256768
ISSN
0021-9258
Appears in Collections:
의과대학 > 미생물학교실 > Articles
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE