Journal of Biological Chemistry
Journal of Biological Chemistry
5 years ago

C/EBPα is Regulated by the RANK Cytoplasmic IVVY535-538 Motif and Stimulates Osteoclastogenesis more Strongly than c-Fos.

Yi-Ping Li, Xu Feng, Joel Jules, Wei Chen
Binding of RANKL to its receptor RANK on osteoclast (OC) precursors upregulates c-Fos and C/EBPα, two critical OC transcription factors. However, the effects of c-Fos and C/EBPα on osteoclastogenesis have not been compared. Herein, we demonstrate that overexpression of c-Fos or C/EBPα in OC precursors upregulates OC genes and initiates osteoclastogenesis independently of RANKL. However, while C/EBPα upregulated c-Fos, c-Fos failed to upregulate C/EBPα in OC precursors. Consistently, C/EBPα overexpression more strongly promoted OC differentiation than did c-Fos overexpression. RANK has a cytoplasmic IVVY535-538 (IVVY) motif that is essential for osteoclastogenesis, and we found that mutation of the IVVY motif blocked OC differentiation by partly inhibiting expression of C/EBPα but not expression of c-Fos. We therefore hypothesized that C/EBPα overexpression might rescue osteoclastogenesis in cells expressing the mutated IVVY motif. However, overexpression of C/EBPα or c-Fos failed to stimulate osteoclastogenesis in the mutant cells. Notably, the IVVY motif mutation abrogated OC gene expression compared with a vector control, suggesting that the IVVY motif might counteract OC inhibitors during osteoclastogenesis. Consistently, the IVVY motif mutant triggered upregulation of RBP-J protein, a potent OC inhibitor. Mechanistically, C/EBPα or c-Fos overexpression in the mutant cells failed to control the upregulated RBP-J expression, leading to suppression of OC genes. Accordingly, RBP-J silencing in the mutant cells rescued osteoclastogenesis with C/EBPα or c-Fos overexpression, with C/EBPα exhibiting a stronger osteoclastogenic effect. Collectively, our findings indicate that C/EBPα is a stronger inducer of OC differentiation than c-Fos, partly via C/EBPα regulation by the RANK IVVY535-538 motif.

Publisher URL: http://doi.org/10.1074/jbc.M116.736009

DOI: 10.1074/jbc.M116.736009

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