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

Abstract

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.

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

“…Then, IRAK activates TNFR-associated factor 6 (TRAF6), leading to activation of NF-kB and c-Jun N-terminal kinase. In addition, MyD88-and TRAF6-deficient mice displayed hyporesponsiveness to both IL-1 and LPS [32,33].…”

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

“…RANK signaling is mediated by the interaction of the 3 intracellular domains with adapter proteins (the TNF receptorassociated factors [TRAFs], especially TRAF6). The TRAF-binding domains of RANK are important for the RANK-dependent induction of NF-B and JNK (21,23). In addition, the signaling pathways via the transcription factors c-Fos and nuclear factor of activated T cells c1 (NF-ATc1) seem to be important for RANKL-induced osteoclastogenesis, as outlined in recent studies (24)(25)(26).…”

NF-κB and the immune response

“…BCL10 oligomerization has been implicated in IKK activation through a process that involves ubiquitination of NEMO (Zhou et al, 2004). This ubiquitination event appears to be mediated by MALT1, and perhaps TRAF6, although no TCR signaling deficits have been reported in TRAF6-deficient mice (Lomaga et al, 1999;Sun et al, 2004). If this is true however, it is possible that the effect is mediated through the kinase TAK1, which functions in IKK activation downstream of TRAF6 in other pathways.…”