Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown

Objective. To determine whether other glycoprotein 130 (gp130) binding cyto kines can mimic the effects of oncostatin M (OSM) in acting synergistically with interleukin-1 alpha (IL-1 alpha) to induce cartilage collagen breakdo wn and collagenase expression, and to determine which receptors mediate the se effects. Methods. The release of collagen and proteoglycan was assessed in bovine an d human cartilage explant cultures. Messenger RNA (mRNA) and protein produc tion from immortalized human chondrocytes (T/C28a4) was analyzed by Norther n blotting and specific enzyme-linked immunosorbent assays. Collagenase act ivity was measured by bioassay. Cell surface receptors were detected by flo w cytometry. Results. OSM in combination with IL-1 alpha caused a rapid synergistic indu ction of matrix metalloproteinase I mRNA, which was sustained over a 72-hou r period. Flow cytometric analyses detected both the OSM-specific receptor and the gp130 receptor at the chondrocyte cell surface, but failed to detec t the leukemia inhibitory factor receptor (LIFR). Cartilage degradation ass ay's revealed that, of the gp130 binding cytokines, only OSM and IL-6, in t he presence of its soluble receptor (sIL-6R), were able to act synergistica lly with IL-1 alpha to promote collagen release. Conclusion. This study demonstrates that IL-6 can mimic OSM in synergizing with IL-1 alpha to induce chondrocyte-mediated cartilage collagen breakdown and collagenase production. In order to have this effect, IL-6 requires th e presence of its soluble receptor. The apparent absence of LIFR explains w hy other gp130 binding cytokines do not act in synergy with IL-1 alpha. Sin ce OSM, IL-6, and sIL-6R levels have all been shown to be elevated in the r heumatoid joint, our findings suggest that these cytokines may be key media tors of cartilage collagen catabolism in the inflammatory arthritides.