One murine study showed that IFN-γ directly inhibits RANKL-mediated osteoclastogenesis by induction of TNF receptor associated factor-6 (TRAF6) degradation.(47) However, randomized, controlled trials have shown that IFN-γ did not prevent bone loss in patients with rheumatoid arthritis (RA).(48) Moreover, it was demonstrated recently that although IFN-γ can inhibit osteoclast formation directly; it also promotes bone resorption indirectly via antigenic-driven T-lymphocyte activation and subsequent secretion of RANKL and TNF-α so that the net effect of IFN-γ on bone remodeling was bone loss. This evidence concerns the gene TNFSF11 and rheumatoid arthritis.