The treatment of cartilage with mediators initiates the breakdown of proteoglycan followed by collagen. This is accompanied by the modulation of different proteinases and inhibitors that include members of the MMP family and TIMPs. We have evidence that a chondrocyte membrane-associated metalloproteinase cleaves aggrecan. This activity is rapidly induced after stimulation with IL-1 and OSM and is not inhibited by TIMPs-1 and -2 but is inhibited by synthetic MMP inhibitors. This same combination of cytokines also upregulates the collagenases with the subsequent release of collagen fragments, and there is a close correlation between the amount of collagen released and collagenase activity produced. Collagen release can be prevented after treatment with specific inhibitors of MAP kinases, inhibitors of MMP transcription, synthetic metalloproteinase inhibitors, TIMPs and treatment of cartilage with agents that upregulate TIMPs. The results from bovine cartilage culture models show that collagen release occurs when TIMP levels are low, collagenases are upregulated and then subsequently activated.

Objective-To investigate whether interleukin 13 (IL13) could act in a chondroprotective manner and protect cartilage stimulated to resorb with a combination of IL1 and oncostatin M (OSM), in a similar way to the anti-inflammatory cytokine, IL4. Methods-IL13 was added to explant cultures of bovine nasal cartilage stimulated to resorb with IL1 and OSM, and the release of collagen and proteoglycan determined. Collagenolytic and tissue inhibitors of metalloproteinase (TIMP) activities were determined by bioassay. Northern blot analyses were performed to determine the eVects of IL13 on the induction of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, and TIMP-1 gene expression. Results-IL13 can prevent the release of collagen from bovine nasal cartilage in a dose dependent manner. This was accompanied by a concomitant decrease in measurable collagenolytic activity in the culture supernates and an increase in TIMP activity. Northern blot analysis showed that IL13 down regulated MMP-3 and MMP-13 levels but up regulated MMP-1 and TIMP-1 gene expression in bovine nasal chondrocytes at 24 hours. Conclusion-This study showed for the first time that IL13 can block collagen release from resorbing cartilage in a similar manner to IL4. This is accompanied by a reduction in detectable collagenolytic activity, a decrease in MMP-3 and MMP-13 mRNA levels, and an up regulation of TIMP-1 expression.