EXCESS OF METALLOPROTEASES OVER TISSUE INHIBITOR OF METALLOPROTEASE MAY CONTRIBUTE TO CARTILAGE DEGRADATION IN OSTEOARTHRITIS AND RHEUMATOID-ARTHRITIS

BACKGROUND: In an attempt to identify the factor(s) involved in the mo dulation of the degradative pathway of articular cartilage, we previou sly reported a possible imbalance between the levels of biologically a ctive forms of metalloproteases and tissue inhibitor of metalloproteas e (TIMP) in osteoarthritis (OA) cartilage. EXPERIMENTAL DESIGN: We ext ended our analysis on the protein level and the synthesis of stromelys in-1, collagenase, TIMP-1, and TIMP-2 in normal, OA, and RA cartilages , and provided information on the synthesis pattern of these proteins in respect to the action of interleukin-1 (IL-1). These protein concen trations were determined by specific sandwich EIA assays. RESULTS: Thi s study allowed us to establish that the concentration of stromelysin- 1 and collagenase is elevated in both OA and rheumatoid arthritis (RA) cartilages when compared with normal, with significantly higher level s of collagenase found in OA (p < 0.0003) and RA (p < 0.0001), and of stromelysin-1 in RA (p < 0.02). In all cases, the level of stromelysin -1 significantly exceeded (a few 100-fold) the collagenase level. The cartilage TIMP-1 level was notably enhanced only in RA, whereas TIMP-2 was increased in both OA and RA cartilage. RA patients with active di sease had a higher level of metalloproteases and TIMP than those patie nts with inactive disease. Moreover, patients taking steroids alone or in combination with methotrexate had a markedly lower metalloprotease level without any changes in the TIMP-1 level. In culture cartilage e xplants, the synthesis of stromelysin-1 was enhanced in RA cartilage, whereas the level of collagenase was increased both in OA and RA expla nts. When compared with normal patients, the TIMP-1 synthesis was esse ntially unchanged in arthritic explants, whereas the level of TIMP-2 w as decreased in RA explants when compared to OA. IL-1 induced a statis tically significant increased synthesis of metalloproteases with the h ighest level found in arthritic explants. IL-1 also significantly decr eased the TIMP-1 synthesis in OA and RA explants, and the TIMP-2 synth esis in OA. CONCLUSIONS: This study demonstrates that stromelysin-1 is the predominant metalloprotease synthesized in human articular cartil age and that both TIMP-1 and TIMP-2 are present in this tissue. The di fferential regulation of metalloprotease and TIMP syntheses by IL-1 su ggests that this cytokine, during inflammatory conditions, may promote cartilage degradation by creating an imbalance between the level of t hese enzymes and their inhibitors.