TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling

作者：Mark A. Lomaga, Wen‐Chen Yeh, Ildiko Sarosi, G S Duncan, Caren L. Furlonger, Andrea P. Ho, Sean Morony, Charles Capparelli, Gwyneth Y. Van, Steve Kaufman, A. van der Heiden, Annick Itié, Andrew C. Wakeham, Wilson Khoo, Takehiko Sasaki, Zheng Cao, Josef Martin Penninger, Christopher J. Paige, David L. Lacey, Colin Robert Dunstan, W. J. Boyle, David V. Goeddel, Tak W. Mak · 发表于：Genes & Development · 年份：1999 · DOI：10.1101/gad.13.8.1015 · 被引用次数：1277 · 研究领域：NF-κB Signaling Pathways、Bone Metabolism and Diseases、Cytokine Signaling Pathways and Interactions

Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.