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

Teruhito Yamashita, Zhenqiang Yao, Fang Li, Qian Zhang, I. Raul Badell, Edward M. Schwarz, Sunao Takeshita, Erwin F. Wagner, Masaki Noda, Koichi Matsuo, Lianping Xing, Brendan F. Boyce

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Abstract

Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor (TNF). Osteoclast formation induced by these cytokines requires NF-κB p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors. c-Fos induces NFATc1, but the relationship between NF-κB and these other transcription factors in osteoclastogenesis remains poorly understood. We report that RANKL and TNF can induce osteoclast formation directly from NF-κB 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-κB 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 byTNF in vitro.Weconclude that NF-κB controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1. Inhibition of NF-κB should prevent RANKL- and TNF-induced bone resorption.

Original languageEnglish
Pages (from-to)18245-18253
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number25
DOIs
Publication statusPublished - 2007 Jun 22

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yamashita, T., Yao, Z., Li, F., Zhang, Q., Badell, I. R., Schwarz, E. M., Takeshita, S., Wagner, E. F., Noda, M., Matsuo, K., Xing, L., & Boyce, B. F. (2007). NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. Journal of Biological Chemistry, 282(25), 18245-18253. https://doi.org/10.1074/jbc.M610701200