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TRAIL-induced rheumatoid arthritis fibroblast-like synoviocyte proliferation is inhibited by OPG

TNF-α related apoptosis inducing ligand (TRAIL) is a proapoptotic factor that can also induce cell proliferation. The role of TRAIL in rheumatoid arthritis (RA) is still unclear. We investigated the effect of TRAIL on RA fibroblast-like synoviocyte (FLS) proliferation. TRAIL induces RA FLS proliferation in a dose-dependent manner, with a maximum proliferation at 0.5 nmol/l (P < 0.05; n = 5). This proliferation could be prevented by the natural TRAIL inhibitor osteoprotegerin (OPG) and a TRAIL antibody. By flow cytometry, we analyzed TRAIL receptors (DR4, DR5 and DcR2). RA FLS constitutively expressed DR5 (n = 5) and three out five RA FLS expressed DR4. Interestingly, RA FLS proliferate more after TRAIL stimulation when expressing both DR4 and DR5, suggesting a cumulative effect of the two receptors. DR5 receptor mediates the signal-inducing cell proliferation because stimulation with an agonistic anti-DR5 antibody induces RA synoviocyte proliferation (n = 4; P < 0.05). Next, we investigated which cells in the synovium could produce TRAIL and OPG. In RA FLS, TRAIL was detected at the mRNA level after IL-1β and TNF-α stimulation but not at the protein level. OPG was constitutively produced (2 ng/ml) and upregulated by IL-1β (14-fold) and TNF-α (5-fold) but not IL-18. On RA synovial T cells, TRAIL was constitutively expressed. Our results show that TRAIL induces RA FLS proliferation. TRAIL produced on synovial T cells may interact with RA FLS expressing DR4 and DR5 to induce FLS proliferation. OPG inhibits TRAIL induced RA FLS proliferation. This novel propriety of OPG may be another explanation for its bone protective role in RA.

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Morel, J., Audo, R., Deschamps, V. et al. TRAIL-induced rheumatoid arthritis fibroblast-like synoviocyte proliferation is inhibited by OPG. Arthritis Res Ther 6 (Suppl 1), 59 (2004).

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