Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NF-kappa B activation.
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 IkappaBalpha degradation resulting in inhibition of NFkappaB-dependent reporter gene activity. In addition, Rac1 acts upstream of TAK1 to induce NF-kappaB 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-kappaB.
Lee
Na Kyung
NK
Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea. leesy@ewha.ac.kr
Choi
Han Kyung
HK
Kim
Dong-Ku
DK
Lee
Soo Young
SY
D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002461:Cell Line, Transformed; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D053245:RANK Ligand / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D020830:rac1 GTP-Binding Protein; D000099151:MAP Kinase Kinase Kinase 7