MATRIX METALLOPROTEINASES AND JOINT MARKERS RELATED TO RHEUMATOID ARTHRITIS
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Rheumatoid arthritis (RA) is a cryptogenic, destructive and progressive inflammatory articular disease that is accompanied with multiplex joint pain and joint swelling as the predominant symptoms. The characteristic feature of the disease is a series of processes from synovial inflammation to destruction of articular cartilages and bones, and joint markers are used in for determining the activity of destruction and restoration of joint components by analyzing synovial fluids, sera, and others. The authors have analyzed matrix component-related joint markers in the synovial fluids of patients with various diseases in the first step and determined the concentration of joint markers, the number of MMPs-positive cells in synovial tissues, and the histological evaluation index of synovial membranes in individual RA cases. Hyaluronic acid (HA) in the collected synovial fluids is determined by the Morgan-Elson method, chondroitin tetrasulf ate (C4S) and hexasulf ate (C6S) by HPLC, and pCOL II -C (chondrocalcin ) and keratan sulfate (KS) by the ETA method. In addition, KS in sera is measured by the ETA method. Synovial tissues were collected during entire prosthetic knee joint replacement or synovectomy under an arthroscope ; the synovial membranes were subjected to immunohisto-chemical staining by H-E and ABC methods ; and the MMPs (MMP-1, 3, 8, and 9) -positive cells thus stained were counted. Synovial histological evaluation index is an inflammation score calculated from five parameters excluding fibrosis out of the six parameters used in the method of Rooney et al., (synoviocyte hyperplasia, fibrosis, proliferating blood vessels, perivascular infiltrates of lymphocytes, focal aggregates of lymphocytes, and diffuse infiltrates of lymphocytes) . A significant difference in the values of HA, C4S, C6S/C4S, and C6S/ HA of osteoarthritis (OA) synovial fluids and in the values of HA, C4S, C6S, and C6S/C4S in RA synovial fluids from synovial fluids of normal healthy subjects were observed. A drop in HA concentration seemed to result from lowered production in synovial tissues, accumulation of synovial fluid, and others. In addition, a high concentration of C4S was likely caused by enhanced production of C4S in synoviocytes or accelerated effusion of blood components. H-E staining revealed that RA synovial membranes grew in the villus-like shape and the cortical cells in the multilayer structure. Neutrophils, macrophages, and lymphocytes infiltrated in the diffuse state, as well as in the lymph follicles with a germinal center in the lower layer. In addition, there were observed granulation tissues due to blood vessel hyperplasia, fibroblast growth, and others were observed. In IHC, MMP-1 and 3-positive cells were present in a greater amount in the cortical layer of the synovial membrane, while MMP-8 and 9-positive cells were present throughout the synovial membrane from the cortical layer to the deeper layer. In particular, MMP-8 was more expressed in neutrophils, while MMP-9 was more expressed in neutrophils, monocytes and osteoclasts of granulation tissues. There were significant differences in MMPs (MMP-1, 3, 8, and 9) and inflammation scores between OA and RA. These differences seem to be related to the fact that cartilage destruction is predominant in rheumatoid arthritis while cartilage destruction and regeneration proceed simultaneously in osteoarthritis. Although MMP-3 in RA is considered to be possibly a reflection of synovitis, there was no correlation with HA. The fact suggests that HA is not necessarily a joint marker indicating inflammation. Significant correlations among all MMPs, as well as between MMP-1, 3, and 9 and the inflammation score were observed. The findings above suggest that MMPs are cooperatively involved in the destruction of RA joints.