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Modulation of the catabolic effects of interleukin‐1β on human articular chondrocytes by transforming growth factor‐β

The effects of IL‐1β and TGF‐β on the biosynthesis of extracellular matrix structural components relative to the metalloproteinases and their inhibitor TIMP1 in human articular chondrocytes were investigated. It has been proposed that TGF‐β, acting as a positive regulator of matrix accretion, can counteract the increased loss of cartilage matrix induced by IL‐1β. To allow a comparison of their effects on mRNA levels for these different components, quantitation by competitive RT/PCR was employed. This method was found to give reproducible estimates of mRNA levels and the observed effects of IL‐1β and TGF‐β on individual components of this system agree with qualitative data obtained by northern blotting. IL‐1β had a more pronounced effect on aggrecan mRNA levels than on those for type II collagen. Similar quantitative differences were observed between collagenase and stromelysin mRNA levels. TGF‐β generally counteracted the effects of IL‐1β, and new steady state levels were attained within 24 h. However, the reversal of IL‐1β induced suppression of matrix protein mRNA levels appeared more effective than its suppression of the increase in stromelysin and collagenase mRNA levels. Similarly TGF‐β did not reduce the extent of IL‐1β induced secretion of stromelysin at the protein level. TIMP1 mRNA levels were only slightly reduced by IL‐1β; however this cytokine effectively surpressed its induction by TGF‐β. The higher concentrations of TGF‐β and longer exposure times required to overcome the surpressive effects of IL‐1β suggest that the interaction between IL‐1β and TGF‐β in the regulation of TIMP1 expression follows a different mechanism to that operating for the metalloproteinases and matrix proteins. Thus the overall potential of TGF‐β to inhibit proteolysis is attenuated by its much slower effect on TIMP1 mRNA levels. © 1996 Wiley‐Liss, Inc.