Inflammatory osteolysis, as in rheumatoid arthritis (RA), reflects increased osteoclast (OC) activity. OC recruitment is mediated via RANKL interaction with its receptor, RANK. We and others have established that TNF plays a key role in the pathogenesis of inflammatory osteolysis and other forms of inflammation-induced bone loss Central to this proposal are our observations that RANKL and TNF both activate NF-kB and AP-1/cJun signaling pathways, and TNF dramatically stimulates RANKL-induced osteoclastogenesis via. TNFr1. Reduced osteoclastogenesis correlates with diminished NF-kB and c-Jun activation by TNF and RANKL in TNFr1-/- cells. These facts, together with our findings that RANKL and TNF stimulate recruitment of TRAF2 and TRAF6 to their receptors, points to a possible intracellular coupling between these two receptors which, in turn, leads to a super osteoclastic response. Supporting this hypothesis is the fact that RANK utilizes the traditional TNFr-recruiting machinery to activate NF-kB and c-Jun signaling pathways. Taken together, our data point that enhanced osteoclastogenesis (as in inflammatory osteolysis) requires the presence of TNFR1. Therefore, understanding the exact mechanisms by which TNF promotes RANKL-dependent osteoclastogenesis and thus, inflammatory osteopenia, may provide a foundation for developing osteoclast inhibitory strategies. Molecular inhibition of osteoclastogenesis by anti-inflammatory cytokines is under-investigated. IL-4, the major soluble factor secreted by T helper-2 (TH2) lymphocytes, is an anti-inflammatory cytokine and a potent inhibitor of osteoclast differentiation. However, its anti-osteoclastic mechanism is unknown. We provide evidence that IL-4 blocks RANKL-induced NF-kB activation in osteoclast precursors. More importantly, using STAT6-/- cells we find that inhibition of NF-kB activation and osteoclastogenesis by IL-4 is a STAT6-dependent event. Given the inflammatory and osteoclastogenic role of NF-kB and that STAT proteins can act as transcriptional inhibitors, our observations raise the possibility that IL-4 exerts its anti-osteoclastogenic effects via inhibition of RANKL activation of NF-kB and perhaps AP-1 signaling pathways. Understanding the molecular steps of IL-4/STAT6-inhibition of osteoclastogenesis may provide the foundation for controlling inflammatory osteolysis.
Our Specific Aims are to determine: 1) the mechanism(s) by which the TNFr1 signaling pathway stimulates RANKL-mediated osteoclastogenesis, 2) the mechanism(s) by which IL-4 inhibits RANKL-mediated osteoclastogenesis.
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