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Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade

Title
Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade
Authors
Moon J.B.Kim J.H.Kim K.Youn B.U.Ko A.Lee S.Y.Kim N.
Ewha Authors
이수영
SCOPUS Author ID
이수영scopus
Issue Date
2012
Journal Title
Journal of Immunology
ISSN
0022-1767JCR Link
Citation
vol. 188, no. 1, pp. 163 - 169
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
SHIP is an SH2-containing inositol-5-phosphatase expressed in hematopoietic cells. It hydrolyzes the PI3K product PI(3,4,5)P 3and blunts the PI3K-initiated signaling pathway. Although the PI3K/Akt pathway has been shown to be important for osteoclastogenesis, the molecular events involved in osteoclast differentiation have not been revealed. We demonstrate that Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. Inhibition of the PI3K by LY294002 reduces formation of osteoclasts and attenuates the expression of NFATc1, but not that of c-Fos. Conversely, overexpression of Akt in bone marrow-derived macrophages (BMMs) strongly induced NFATc1 expression without affecting c-Fos expression, suggesting that PI3K/Akt-mediated NFATc1 induction is independent of c-Fos during RANKL-induced osteoclastogenesis. In addition, we found that overexpression of Akt enhances formation of an inactive form of GSK3β (phospho-GSK3β) and nuclear localization of NFATc1, and that overexpression of a constitutively active form of GSK3β attenuates osteoclast formation through downregulation of NFATc1. Furthermore, BMMs from SHIP knockout mice show the increased expression levels of phospho-Akt and phospho-GSK3β, as well as the enhanced osteoclastogenesis, compared with wild type. However, overexpression of a constitutively active form of GSK3β attenuates RANKL-induced osteoclast differentiation from SHIP-deficient BMMs. Our data suggest that the PI3K/Akt/GSK3β/NFATc1 signaling axis plays an important role in RANKL-induced osteoclastogenesis. Copyright © 2011 by The American Association of Immunologists, Inc.
DOI
10.4049/jimmunol.1101254
Appears in Collections:
자연과학대학 > 생명과학전공 > Journal papers
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