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 modulation of the degradative pathway of articular cartilage, we previously reported a possible imbalance between the levels of biologically active forms of metalloproteases and tissue inhibitor of metalloprotease (TIMP) in osteoarthritis (OA) cartilage.

EXPERIMENTAL DESIGN

We extended our analysis on the protein level and the synthesis of stromelysin-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 concentrations were determined by specific sandwich EIA assays.

RESULTS

This 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 levels 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 disease had a higher level of metalloproteases and TIMP than those patients 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 explants, the synthesis of stromelysin-1 was enhanced in RA cartilage, whereas the level of collagenase was increased both in OA and RA explants. When compared with normal patients, the TIMP-1 synthesis was essentially unchanged in arthritic explants, whereas the level of TIMP-2 was decreased in RA explants when compared to OA. IL-1 induced a statistically significant increased synthesis of metalloproteases with the highest level found in arthritic explants. IL-1 also significantly decreased the TIMP-1 synthesis in OA and RA explants, and the TIMP-2 synthesis in OA.

CONCLUSIONS

This study demonstrates that stromelysin-1 is the predominant metalloprotease synthesized in human articular cartilage and that both TIMP-1 and TIMP-2 are present in this tissue. The differential regulation of metalloprotease and TIMP syntheses by IL-1 suggests that this cytokine, during inflammatory conditions, may promote cartilage degradation by creating an imbalance between the level of these enzymes and their inhibitors.