Rheumatoid synovial fluid contains bioactive leukemia inhibitory factor with cartilage degrading activity - Another target for chondroprotective intervention

Objective, To determine if the procatabolic activity of inflammatory synovi al fluids (SF) from patients with rheumatoid arthritis (RA) could be attenu ated by the cytokine antagonists murine leukemia inhibitory factor (LIF) bi nding protein (mLBP) and interleukin 1 receptor antagonist (IL-1ra). Methods. Pig articular cartilage explants were cultured in the presence of either 20% v/v rheumatoid (RA) or osteoarthritic (OA) SF and varying concen trations of either mLBP and/or IL-1ra. The catabolic activity of the SF and the relative effects of mLBP and/or IL-1ra were assessed by determining th e percentage release of sulfated glycosaminoglycans from cartilage explants . LIF concentrations were measured by ELISA. Results. RA SF but not OA SF stimulated release of proteoglycans from pig c artilage explants in vitro (47.3 +/- 2.2% vs 24.6 +/- 2.0%; p < 0.0001). Mu rine LBP at 100 ng/ml and recombinant human (rh) IL-1ra at 5000 ng/ml produ ced a dose dependent inhibition of this proteoglycan release (p < 0.0067 an d p < 0.0111, respectively). The RA SF stimulated proteoglycan release was attenuated by mLBP and rhIL-1ra independently. No additive effect of this a ttenuation was observed when maximal inhibitory doses were used in combinat ion. The decrease in proteoglycan release produced by mLBP correlated signi ficantly with LIF concentrations in RA SE Conclusion. These findings are consistent with the concept that IL-1 stimul ates cartilage proteoglycan resorption in RA. They also support the hypothe sis that LIF, too, contributes to cartilage proteoglycan resorption in RA. The residual stimulation not accounted for by IL-1 or LIF suggests other cy tokines may contribute. The role of LIF and related or unrelated cytokines may need to be taken into account to optimize chondroprotection in RA and o ther rheumatic diseases.