Relationships of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis

Objective. To determine interrelationships in matrix turnover in articular cartilage and joint inflammation in rheumatoid arthritis (RA). Methods. Synovial fluid was obtained from the knees of 63 RA patients; radi ographs were evaluated to determine the RA stage. Concentrations of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), the 846 epitope, and the keratan sulfate (KS) epitope of aggrecan, the C-p ropeptide of cartilage type II procollagen (CPII; biosynthetic marker), the cleavage of type II collagen by collagenase (CIIC; generated neoepitope), and polymorphonuclear leukocyte elastase (PMNE; inflammation marker) were m easured by immunoassay. Concentrations of the unsaturated disaccharides of hyaluronic acid (Adi-HA) and the proteoglycan glycosaminoglycan disaccharid es of chondroitins 4 and 6 sulfate (Delta di-C4S and Delta di-C6S) were det ermined by high-performance liquid chromatography. Results. MMP-3 was markedly increased in RA compared with osteoarthritis. I ncreases in TIMP-1 in RA were less pronounced and were inversely correlated with MMP-3 levels. CIIC was reduced in RA, as was the release of the KS ep itope and Delta di-C6S. In contrast, Delta di-C4S and the 846 epitope were up-regulated. PMNE levels correlated with the 846 epitope and Delta di-C4S, and more strongly with TIMPs 1 and 2. The changes may signify attempts at control of proteolysis in parallel with increased aggrecan turnover, which would favor matrix assembly. PMNE also correlated with MMP-9, and MMP-9 cor related with CPII. The Delta di-HA level was decreased in RA and was invers ely correlated with CPII and MMP-9 as well as with MMPs 2 and 3. In contras t, Delta di-HA was directly correlated with TIMP-1 and the 846 epitope. The se observations suggest that RA and PMNs may be involved in the control of proteolysis and cartilage proteoglycan assembly. Conclusion. Our observations provide new insights into the complex changes in cartilage turnover and PMN influx in RA joints.