Effect of thrombin inhibition on synovial inflammation in antigen induced arthritis

Abstract

OBJECTIVE To determine the effect of the thrombin inhibitor, hirudin, on the pathogenesis of murine antigen induced arthritis (AIA). METHODS AIA was induced by intra-articular injection of methylated bovine serum albumin in the knee joints of previously immunised mice. Hirudin (injected subcutaneously 3 × 200 μg/mouse/day) was given over 13 days, starting three days before arthritis onset, and its anticoagulant effect monitored by clotting times. Arthritis severity was evaluated by technetium-99m (^99mTc) uptake in the knee joints and by histological scoring. In addition, intra-articular fibrin deposition was examined by immunohistochemistry, and synovial cytokine mRNA expression measured by RNase protection. RESULTS Joint inflammation, measured by ^99mTc uptake, was significantly reduced in hirudin treated mice at days 7 and 10 after arthritis onset. Histologically, synovial thickness was markedly decreased in hirudin treated mice compared with untreated ones. By contrast, no difference in articular cartilage proteoglycan content was found between both groups. Intra-articular fibrin deposition and synovial interleukin 1β mRNA levels, were slightly reduced (∼20%) in arthritic joints from hirudin treated mice compared with untreated ones at day 10 of AIA. CONCLUSION Hirudin reduces joint inflammation associated with AIA by fibrin-dependent and independent mechanisms.