Strength of TRAF6 signalling determines osteoclastogenesis.
TRANCE/TRAF6 signalling governs osteoclastogenesis in vivo. Only the TRANCE receptor (TRANCE-R) has been shown to induce osteoclastogenesis, even though other immune receptors, including CD40 and IL-1R/Toll-like receptor, use TRAF6 to activate overlapping signalling cascades. These observations led us to question whether qualitative or quantitative differences exist between the TRAF6-mediated signals induced by TRANCE and by other ligand-receptor pairs. Here we show that stimulation by overexpressed wild-type CD40 can induce osteoclastogenesis. Stimulation through modified CD40 containing increased numbers of TRAF6-binding sites in the cytoplasmic tails showed a dose-dependent increase in the activation of p38 kinase and more pronounced osteoclastogenesis. Moreover, precursors overexpressing TRAF6 differentiate into osteoclasts in the absence of additional signals from TRANCE. Our results suggest that differences in the osteoclastogenesis-inducing capacity of TRANCE-R versus other TRAF6-associated receptors may in part stem from a quantitative difference in the TRAF6-mediated signals.
Kadono
Yuho
Y
Department of Pathology & Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 308 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
Okada
Fumihiko
F
Perchonock
Claire
C
Jang
Hyun Duk
HD
Lee
Soo Young
SY
Kim
Nacksung
N
Choi
Yongwon
Y
D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
D019013:CD40 Antigens; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6