NFATc1 Induces Osteoclast Fusion via Up-Regulation of Atp6v0d2 and the Dendritic Cell-Specific Transmembrane Protein (DC-STAMP)

Mol Endocrinol. 2008 Jan;22(1):176-85. doi: 10.1210/me.2007-0237. Epub 2007 Sep 20.

Abstract

NFATc1 has been characterized as a master regulator of nuclear factor kappaB ligand-induced osteoclast differentiation. Herein, we demonstrate a novel role for NFATc1 as a positive regulator of nuclear factor kappaB ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-alpha. Exogenous overexpression of a constitutively active form of NFATc1 in bone marrow-derived monocyte/macrophage cells (BMMs) induces formation of multinucleated osteoclasts as well as the expression of fusion-mediating molecules such as the d2 isoform of vacuolar ATPase V(o) domain (Atp6v0d2) and the dendritic cell-specific transmembrane protein (DC-STAMP). Moreover, inactivation of NFATc1 by cyclosporin A treatment attenuates expression of Atp6v0d2 and DC-STAMP and subsequent fusion process of osteoclasts. We show that NFATc1 binds to the promoter regions of Atp6v0d2 and DC-STAMP in osteoclasts and directly induces their expression. Furthermore, overexpression of Atp6v0d2 and DC-STAMP rescues cell-cell fusion of preosteoclasts despite reduced NFATc1 activity. Our data indicate for the first time that the NFATc1/Atp6v0d2 and DC-STAMP signaling axis plays a key role in the osteoclast multinucleation process, which is essential for efficient bone resorption.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Fusion
  • Dendritic Cells / cytology
  • Dendritic Cells / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • NFATC Transcription Factors / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proton-Translocating ATPases / genetics
  • Proton-Translocating ATPases / metabolism*
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DC-STAMP protein, mouse
  • Membrane Proteins
  • NFATC Transcription Factors
  • Nerve Tissue Proteins
  • RANK Ligand
  • Proton-Translocating ATPases