NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1

J Biol Chem. 2007 Jun 22;282(25):18245-53. doi: 10.1074/jbc.M610701200. Epub 2007 May 7.

Abstract

Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor (TNF). Osteoclast formation induced by these cytokines requires NF-kappaB p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors. c-Fos induces NFATc1, but the relationship between NF-kappaB and these other transcription factors in osteoclastogenesis remains poorly understood. We report that RANKL and TNF can induce osteoclast formation directly from NF-kappaB p50/p52 double knockout (dKO) osteoclast precursors when either c-Fos or NFATc1 is expressed. RANKL- or TNF-induced c-Fos up-regulation and activation are abolished in dKO cells and in wild-type cells treated with an NF-kappaB inhibitor. c-Fos expression requires concomitant RANKL or TNF treatment to induce NFATc1 activation in the dKO cells. Furthermore, c-Fos expression increases the number and resorptive capacity of wild-type osteoclasts induced by TNF in vitro. We conclude that NF-kappaB controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1. Inhibition of NF-kappaB should prevent RANKL- and TNF-induced bone resorption.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • NF-kappa B p50 Subunit / physiology*
  • NF-kappa B p52 Subunit / physiology*
  • NFATC Transcription Factors / metabolism*
  • Osteoblasts / cytology*
  • Osteoclasts / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RANK Ligand / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation*

Substances

  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Tumor Necrosis Factor-alpha