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

Abstract

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; radiographs 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‐propeptide 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 measured by immunoassay. Concentrations of the unsaturated disaccharides of hyaluronic acid (Δdi‐HA) and the proteoglycan glycosaminoglycan disaccharides of chondroitins 4 and 6 sulfate (Δdi‐C4S and Δdi‐C6S) were determined by high‐performance liquid chromatography. Results MMP‐3 was markedly increased in RA compared with osteoarthritis. Increases 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 epitope and Δdi‐C6S. In contrast, Δdi‐C4S and the 846 epitope were up‐regulated. PMNE levels correlated with the 846 epitope and Δdi‐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 correlated with CPII. The Δdi‐HA level was decreased in RA and was inversely correlated with CPII and MMP‐9 as well as with MMPs 2 and 3. In contrast, Δdi‐HA was directly correlated with TIMP‐1 and the 846 epitope. These observations suggest that HA 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.

Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down‐regulation by tumor necrosis factor α blockade in spondylarthropathy

“…Although the present study was not designed to assess the complex functional interactions between proenzymes, activated MMP forms, and inhibitory TIMPs (38), the similar expression of the MMP/TIMP system in SpA and RA might suggest that it is equally involved in local disease features in both diseases. Indeed, the demonstration of MMP-9 in intravascular cells, in the vessel wall, and around the vessels, as well as the correlations between the expression of MMPs 2, 3, and 9 and the degree of vascularity in the present study suggest that the previously demonstrated involvement of these mediators in angiogenesis (39-42) also applies to inflamed synovium in SpA.…”

Hyaluronate Inhibits the Interleukin-1.BETA.-Induced Expression of Matrix Metalloproteinase (MMP)-1 and MMP-3 in Human Synovial Cells

“…Indeed, elevated protein and/or mRNA levels of MMP-1 and MMP-3 have been detected in synovial fluid and membrane (Gravallese et al 1991;Yoshihara et al 2000). Furthermore, the production of TIMP-1 and TIMP-2 in synovial fluid is also high in rheumatoid arthritis compared with normal synovial fluid, but not as high as MMPs (Ishiguro et al 2001). As a result of such an MMP-to-TIMP imbalance, degradation of bone and cartilage are accelerated (Burger et al 1998).…”

Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis

“…KS, an index of proteoglycan catabolism, was quantified by inhibition RIA using the monoclonal antibody AN9P1 Fab fragment, 125 Ilabeled adult human aggrecan as a tracer, and unlabeled aggrecan as the standard (2,21). The amino-terminal (TC A ) fragment cleaved by collagenase from triple-helical type II collagen includes (at its carboxy terminus) the neoepitope Col2-3/4C long mono , which was measured using a competitive inhibition monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) (7,8,23,24). All of these epitopes are present in canine articular cartilage and their extracts and in canine body fluids, as determined by immunohistochemistry (see below) and Western blotting.…”