Background: TNF receptor-associated factor 2 (TRAF2) is a key adaptor molecule in the TNF receptor (TNFR) signaling pathway. Results: TRAF-interacting protein (TRIP) inhibits Lys63 -linked TRAF2 ubiquitination by blocking the binding of the cofactor sphingosine 1-phosphate (S1P) to the TRAF2 RING domain. Conclusion: TRIP negatively regulates the TRAF2 ubiquitin-dependent pathway by modulating the TRAF2-S1P interaction. Significance: TRIP is an important cellular regulator of the TNFR-mediated inflammatory response.

Background: Genetic defects in the OSTM1 (osteopetrosis-associated transmembrane protein 1) gene cause autosomal recessive osteopetrosis. Results:The loss of the transmembrane domain in the OSTM1 gene produces a secreted form of truncated OSTM1 that inhibits osteoclast differentiation and survival. Conclusion: Extracellular secretion of a truncated OSTM1 is negatively involved in osteoclastogenesis. Significance: We identified a novel function for the secreted form of truncated OSTM1 in osteoclastogenesis.

We have shown that D-chiro-inositol is negatively involved in osteoclastogenesis through the inhibition of multinucleated OC formation by cell-cell fusion. The expression of NFATc1 was significantly down-regulated by D-chiro-inositol in OCs and consequently, the expression of OC marker genes was significantly reduced. Hence, these results show that D-chiro-inositol might be a good candidate to treat inflammatory bone-related diseases or secondary osteoporosis in diabetes mellitus.

The signaling pathway downstream of stimulation of receptor activator of nuclear factor B (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANK cyto ) to trigger downstream osteoclastogenic signaling cascades. RANK cyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANK cyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANK cyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANK cyto enhances downstream NF-B, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.The integrity of the skeletal system is maintained by the process of bone remodeling, in which old and damaged bone is continuously replaced with new bone through the balanced action of bone-resorbing osteoclasts (OCs) 3 and bone-forming osteoblasts (1-3). As the only cells with bone-resorbing activity, OCs are clinically important in bone-related diseases; accelerated bone destruction by OCs results in pathological bone loss associated with rheumatoid arthritis, multiple myeloma, metastatic cancer, and osteoporosis, whereas impaired function of OCs leads to osteopetrotic disorders (2, 4).OCs are multinucleated giant cells that are formed by the fusion of monocyte/macrophage lineage precursors through the process of OC differentiation or osteoclastogenesis (2). The signaling pathways of receptor activator of nuclear factor B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play key roles in osteoclastogenesis (2, 5). Mice lacking either RANK or RANKL exhibit severe osteopetrotic phenotypes, highlighting the importance of RANK-RANKL signaling as a crucial regulator of OC differentiation, activation, and survival (6, 7). RANK-RANKL signaling is initiated primarily by the recruitment of cytoplasmic TNF receptor-associated factors (TRAFs) that trigger the activation of signaling cascades downstream of adaptors/kinases, such as nuclear fa...

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