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

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 indu ced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TN F) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we repo rt that mice deficient in TNF receptor-associated factor 6 (TRAF6) are oste opetrotic with defects in bone remodeling and tooth eruption due to impaire d 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 perina tal and postnatal survival. These findings establish unexpectedly diverse a nd critical roles for TRAF6 in perinatal and postnatal survival, bone metab olism, LPS, and cytokine signaling.