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Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade.
J Immunol. 2012 Jan 01; 188(1):163-9.JI

Abstract

SHIP is an SH2-containing inositol-5-phosphatase expressed in hematopoietic cells. It hydrolyzes the PI3K product PI(3,4,5)P(3) and 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.

Authors+Show Affiliations

Chonnam National University Medical School, Gwangju, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22131333

Citation

Moon, Jang Bae, et al. "Akt Induces Osteoclast Differentiation Through Regulating the GSK3β/NFATc1 Signaling Cascade." Journal of Immunology (Baltimore, Md. : 1950), vol. 188, no. 1, 2012, pp. 163-9.
Moon JB, Kim JH, Kim K, et al. Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. J Immunol. 2012;188(1):163-9.
Moon, J. B., Kim, J. H., Kim, K., Youn, B. U., Ko, A., Lee, S. Y., & Kim, N. (2012). Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. Journal of Immunology (Baltimore, Md. : 1950), 188(1), 163-9. https://doi.org/10.4049/jimmunol.1101254
Moon JB, et al. Akt Induces Osteoclast Differentiation Through Regulating the GSK3β/NFATc1 Signaling Cascade. J Immunol. 2012 Jan 1;188(1):163-9. PubMed PMID: 22131333.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. AU - Moon,Jang Bae, AU - Kim,Jung Ha, AU - Kim,Kabsun, AU - Youn,Bang Ung, AU - Ko,Aeran, AU - Lee,Soo Young, AU - Kim,Nacksung, Y1 - 2011/11/30/ PY - 2011/12/2/entrez PY - 2011/12/2/pubmed PY - 2012/2/18/medline SP - 163 EP - 9 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 188 IS - 1 N2 - SHIP is an SH2-containing inositol-5-phosphatase expressed in hematopoietic cells. It hydrolyzes the PI3K product PI(3,4,5)P(3) and 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/22131333/Akt_induces_osteoclast_differentiation_through_regulating_the_GSK3β/NFATc1_signaling_cascade_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=22131333 DB - PRIME DP - Unbound Medicine ER -