Signaling by tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is essential for the differentiation of monocytes/ macrophages into osteoclasts. We show here that TRANCE selectively activates Rac1, but not Rac2 in osteoclast precursors. Expression of a dominant interfering mutant of TNF receptor-associated factor (TRAF)6 blocks TRANCE-mediated Rac1 activation, indicating that Rac1 lies downstream of TRAF6. Osteoclast precursors expressing a dominant negative Rac1N17 are defective in TRANCE-induced IKK activation and IκBα degradation resulting in inhibition of NFκB-dependent reporter gene activity. In addition, Rac1 acts upstream of TAK1 to induce NF-κB activation and is required for the normal differentiation of osteoclast precursors. Thus, Rac1 may represent a key regulator for differentiation of osteoclasts through the activation of NF-κB.
Bibliographical noteFunding Information:
We thank J. Kim for critical reading of the manuscript, G. Bokoch for providing the Rac2 Ab, J. Inoue for provid- ing the pMX-TRAF6 vectors, T. Kitamura for providing the Plat-E cell line and pMXs vectors, E. Eynon for providing the RacN17 vectors, T. Ishitani for providing the TAK1 vectors, and Y. Choi for providing the 3T3 TRAF6−/− cells. This work was supported by Korea Research Foundation Grant (KRF-2000-015-FS0006) (to S.Y.L.).
- Osteoclast differentiation
- Signaling cascades