MHC class II transactivator negatively regulates RANKL-mediated osteoclast differentiation by downregulating NFATc1 and OSCAR

Cell Signal. 2010 Sep;22(9):1341-9. doi: 10.1016/j.cellsig.2010.05.001. Epub 2010 May 11.

Abstract

Nuclear factor of activated T cells (NFAT) c1 plays a key role in receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation and function via induction of osteoclast-specific target genes including osteoclast-associated receptor (OSCAR), cathepsin K, and tartrate-resistant acid phosphatase. To elucidate which downstream target genes are regulated by NFATc1 during osteoclastogenesis, we used microarray analyses to examine gene expression profiles in the context of bone marrow-derived macrophages overexpressing a constitutively active form of NFATc1. Herein, we demonstrate that MHC class II transactivator (CIITA) is up-regulated downstream of NFATc1. Overexpression of CIITA in osteoclast precursors attenuates RANKL-induced osteoclast formation through down-regulation of NFATc1 and OSCAR. Epigenetic overexpression of CIITA regulates NFATc1 and OSCAR by competing with c-Fos and NFATc1 for CBP/p300 binding sites. Furthermore, silencing of CIITA by RNA interference in osteoclast precursors enhances osteoclast formation as well as NFATc1 and OSCAR expression. Taken together, our data reveal that CIITA can act as a modulator of RANKL-induced osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Differentiation
  • Down-Regulation
  • Mice
  • NFATC Transcription Factors / metabolism*
  • Nuclear Proteins / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Proto-Oncogene Proteins c-fos / antagonists & inhibitors
  • RANK Ligand / antagonists & inhibitors*
  • RANK Ligand / pharmacology
  • Receptors, Cell Surface / metabolism*
  • Trans-Activators / metabolism*
  • p300-CBP Transcription Factors / metabolism

Substances

  • MHC class II transactivator protein
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Oscar protein, mouse
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Receptors, Cell Surface
  • Trans-Activators
  • p300-CBP Transcription Factors