The pathophysiological significance of proteases in patients with chronic inflammatory joint disease

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To clarify the pathophysiological significance of proteases in RA and OA, we investigated what kinds of proteases were specifically activated in both synovial fluid and synovial tissue of RA ＆ OA patients , and effects of serine proteases on release of inflammatory cytokines from synovial cells.We obtained the following fmdings. (I) When the protease substrates were incubated with SF supernatants, thrombin was the most preferentially hydrolyzed while trypsin substrate and cathepsin B substrate were hydrolyzed to some degree. In the case of SF cell extracts, cathepsin B substrate was the most preferentially hydrolyzed while the other substrates were hardly hydrolyzed. In the case of synovial tissue extracts, cathepsin B substrate was the most preferentially hydrolyzed while trypsin substrate was hydrolyzed to some degree. Protease activities were in general significantly higher in RA than in OA. (II) Thrombin (0.1 to 100 units /ml) significantly enhanced growth of the synovial fibroblast-like cells (FC). When SFC were cultured with thrombin (100 units/ml) or MCT (10 ng/ml), concentrations of IL-8 and IL-6 in the culture medium were significantly increased compared with the control, while the concentrations of IL-1□, IL-1□ and TNF-□ were not detectable in all the culture mediums. (III) Cathepsin B-like protease purified from both the SF and synovial tissues ofRA patients was mainly composed of cathepsin B, and the cathepsin B purified from SF samples ofRA patients was capable of activating prourokinase to urokinase in vitro.