NF-{kappa}B p50 and p52 Regulate Receptor Activator of NF-{kappa}B Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1

Department of Microbiology and Immunology, Keio University, Edo, Tōkyō, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2007; 282(25):18245-53. DOI: 10.1074/jbc.M610701200
Source: PubMed


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 by TNF in vitro. We conclude 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.

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    • "RANKL stimulates the expression and activation of NFATc1 in osteoclast precursors by regulating other transcription factors. It has been shown that RANKL-induced NFATc1 expression depends on NF-κB and c-Fos, which are activated by RANKL [9, 12]. It was also reported that RANKL suppresses the expression of transcriptional repressors such as inhibitors of differentiation/DNA binding (Ids), v-maf musculoaponeurotic fibrosarcoma oncogene family protein B (MafB), and interferon regulatory factor 8 that inhibit NFATc1 expression and osteoclast differentiation [13]. "
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    • "Mice lacking both of the NF-κB p50 and p52 subunits develop osteoporosis due to defective osteoclast development [31]. In addition, it was reported that NF-κB p50/p52 double knockout osteoclast precursors fail to induce c-Fos and NFATc1 expression in response to RANKL, and overexpression of c-Fos rescues the defect in osteoclast differentiation in NF-κB p50/p52 double knockout osteoclast precursors [5]. The classical NF-κB signaling pathway involves IκB kinase (IKK) complex-mediated phosphorylation and degradation of IκBα which allows NF-κB heterodimer containing the p65 and p50 subunits to translocate to the nucleus and activate transcription of target genes [32]. "
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    • "Binding of RANKL to RANK activates several transcription factors responsible for promoting osteoclastic gene expression. These are not all activated within the same time frame: early response factors, such as AP-1 (c-Fos/c-Jun dimer), are activated before late-response factors, such as NFATc1 [34]. Furthermore, AP-1 is known to regulate the expression of NFATc1 by binding to the NFATc1 promoter [35]. "
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