TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation.
Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.
Department of General Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Men-Luh
ML
Yen
Ping-Ning
PN
Hsu
Hsiu-Jung
HJ
Liao
Be-Hang
BH
Lee
Hwei-Fang
HF
Tsai
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D054875:Ubiquitination
D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human