Cytokines, including receptor activator of nuclear factor kappa B ligand (RANKL) and TNF, induce increased osteoclast (OC) formation and bone loss in postmenopausal osteoporosis and inflammatory arthritides. RANKL and TNF can independently induce OC formation in vitro from WT OC precursors via TNF receptor-associated factor (TRAF) adaptor proteins, which bind to their receptors. Of these, only TRAF6 is required for RANKL-induced osteoclastogenesis in vitro. However, the molecular mechanisms involved remain incompletely understood. Here, we report that RANKL induced formation of bone-resorbing OCs from TRAF6-/- OC precursors when cultured on bone slices, but not on plastic. The mechanisms involved increased TNF production by TRAF6-/- OC precursors resulting from their interaction with bone matrix and release of active TGF beta from the resorbed bone, coupled with RANKL-induced autophagolysosomal degradation of TRAF3, a known inhibitor of OC formation. Consistent with these findings, RANKL enhanced TNF-induced OC formation from TRAF6-/- OC precursors. Moreover, TNF induced significantly more OCs from mice with TRAF3 conditionally deleted in myeloid lineage cells, and it did not inhibit RANKL-induced OC formation from these cells. TRAF6-/- OC precursors that over-expressed TRAF3 or were treated with the autophagolysosome inhibitor, chloroquine, formed significantly fewer OCs in response to TNF alone or in combination with RANKL. We conclude that RANKL can enhance TNF-induced OC formation independently of TRAF6 by degrading TRAF3. These findings suggest that preventing TRAF3 degradation with drugs like chloroquine could reduce excessive OC formation in diseases in which bone resorption is increased in response to elevated production of these cytokines.
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