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

Lookup NU author(s): Emeritus Professor Drew Rowan, Paul Koshy, Dr William Shingleton, Dr Beverley Degnan, Emeritus Professor Tim Cawston


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Objective. To determine whether other glycoprotein 130 (gp130) binding cytokines can mimic the effects of oncostatin M (OSM) in acting synergistically with interleukin-1 alpha (IL-1 alpha) to induce cartilage collagen breakdown and collagenase expression, and to determine which receptors mediate these effects. Methods. The release of collagen and proteoglycan was assessed in bovine and human cartilage explant cultures. Messenger RNA (mRNA) and protein production from immortalized human chondrocytes (T/C28a4) was analyzed by Northern blotting and specific enzyme-linked immunosorbent assays. Collagenase activity was measured by bioassay. Cell surface receptors were detected by flow cytometry. Results. OSM in combination with IL-1 alpha caused a rapid synergistic induction of matrix metalloproteinase I mRNA, which was sustained over a 72-hour period. Flow cytometric analyses detected both the OSM-specific receptor and the gp130 receptor at the chondrocyte cell surface, but failed to detect the leukemia inhibitory factor receptor (LIFR). Cartilage degradation assay's revealed that, of the gp130 binding cytokines, only OSM and IL-6, in the presence of its soluble receptor (sIL-6R), were able to act synergistically 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 the presence of its soluble receptor. The apparent absence of LIFR explains why other gp130 binding cytokines do not act in synergy with IL-1 alpha. Since OSM, IL-6, and sIL-6R levels have all been shown to be elevated in the rheumatoid joint, our findings suggest that these cytokines may be key mediators of cartilage collagen catabolism in the inflammatory arthritides.

Publication metadata

Author(s): Rowan AD, Koshy PJT, Shingleton WD, Degnan BA, Heath JK, Vernallis AB, Spaull JR, Life PF, Hudson K, Cawston TE

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatism

Year: 2001

Volume: 44

Issue: 7

Pages: 1620-1632

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/1529-0131(200107)44:7<1620::AID-ART285>3.0.CO;2-B


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