TNF is a dominant inflammatory cytokine that is over-produced in the joints of patients with rheumatoid arthritis, as well as animal models of this disease. It promotes bone destruction and inflammation through stimulation of osteoclast formation and activation. While it has been established that the RANKL/RANK system is essential for TNF-induced osteoclast formation and bone erosion in vivo, its role in TNF-induced inflammation remains poorly understood and controversial. Here, we report that genetic and biologic disruption of the RANKL/RANK signaling eliminates knee joint inflammation in TNF-Tg/RANKL-/-, TNF-Tg/RANK-/- and RANK:Fc treated-TNF-Tg mice as determined by functional assessments and histomorphometry. Among several potential mechanisms that could be responsible for this decrease in inflammation, we found that RANKL synergizes with TNF to stimulate TNF production by osteoclast precursors. Thus, blockade of RANKL/RANK signaling may be a viable therapeutic strategy to prevent inflammation and bone loss in diseases where elevated TNF is a key pathogenic factor.
Open Peer Review Details | |||
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Manuscript submitted on 31-12-2008 |
Original Manuscript | Disruption of Rankl/Rank Signaling Reduces TNF-Induced Joint Inflammation In Vivo |