cIAP1/2 negatively regulate RANKL-induced osteoclastogenesis through the inhibition of NFATc1 expression

Genes Cells. 2012 Dec;17(12):971-81. doi: 10.1111/gtc.12012. Epub 2012 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line
  • Gene Expression Regulation
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology
  • Monocytes / metabolism
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • RANK Ligand / metabolism*
  • RNA, Messenger / biosynthesis
  • RNA, Small Interfering

Substances

  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • RNA, Messenger
  • RNA, Small Interfering
  • Tnfsf11 protein, mouse