Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction between Smad3 and Traf6

RANKL plays a central role in osteoclast differentiation. The binding of RANKL to its receptor RANK activates JNK and Map38 signaling pathways, which leads to the differenciation, activation and survival of osteoclasts. Molecular mechanisms underlying the contribution of TGF-β for promoting RANKL induced osteoclastogenesis have not been elucidated. Using a specific inhibitor of TGF-β type 1 receptor kinase activity or introducing a dominant negative type 2 TGF-β receptor, the authors of a recent study [1] almost completely blocked RANKL-induced osteoclastogenesis.

TGF-β is known to activate the Smad signaling pathway. Blockade of this signaling markedly suppressed RANKL-induced osteoclastogenesis. This blockade affected the formation of the TRAF6-TAB1-TAK1 complex induced by the RANKL signaling pathway and necessary for osteoclastogenesis. Immunoprecipitation analysis showed that Smad2/3 complexes interact with TRAF6-TAB1-TAK1 complexes. Using deletion mutant of Smad3, the authors showed that a Smad3 domain, named MH2 domain, is necessary for TRAF6-TAB1-TAK1 complex formation. Additionally, gene silencing of Smad3 in osteoclast precursors suppressed RANKL-induced osteoclast differentiation.

This study showed that TGF-β is mandatory in RANKL-induced osteoclastogenesis through the activation of the Smad signalling and the likely interaction of the Smad3 MH2 domain with TRAF6.

1. Yasui T, et al. J Bone Miner Res. 2011;26:1447-1456.