title: cIAP1/2 negatively regulate RANKL-induced osteoclastogenesis through the inhibition of NFATc1 expression.
abstract: Receptor activator of nuclear factor κB (RANK) is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and triggers osteoclastogenesis by inducing the expression of NFATc1 through the activation of the NF-κB and MAPK pathways. Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2), which are ubiquitin E3 ligases, are involved in the activation of the NF-κB and MAPK pathways by various members of the TNFRSF. However, the involvement of cIAP1/2 in RANK signaling has remained largely unknown. In this study, we reveal the involvement of cIAP1/2 in RANK ligand (RANKL)-induced osteoclastogenesis. The over-expression of cIAP1 or cIAP2 in the mouse monocytic cell line Raw264.7 resulted in the significant suppression of RANKL-induced NFATc1 mRNA expression and osteoclastogenesis, whereas the activation of the NF-κB and MAPK pathways was barely changed by these over-expressions. The depletion of endogenous cIAP1/2 by their specific inhibitor MV1 or their siRNA-mediated knockdown resulted in enhanced RANKL-induced NFATc1 expression and osteoclastogenesis without affecting the activation of the NF-κB and MAPK pathways. In combination, these results indicate that cIAP1/2 negatively regulate osteoclastogenesis by inhibiting NFATc1 mRNA expression in a manner that is distinct from the previously identified functions of cIAP1/2.
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Mami
authors.initials: M
authors.lastname: Yokota
authors.forename: Yuu
authors.initials: Y
authors.lastname: Taguchi
authors.forename: Jin
authors.initials: J
authors.lastname: Gohda
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse