MECHANISM OF THE ANTIOSTEOARTHRITIC ACTION OF ULINASTATIN IN COMPARISON WITH THOSE OF INDOMETHACIN AND TRIAMCINOLONE

We investigated the effect of ulinastatin, a candidate anti-osteoarthritic drug, in comparison with indomethacin and triamcinolone, two well-known drugs for osteoarthritis, on IL-1 production by monocytes, proteoglycan synthesis by chondrocytes and superoxide generation by leukocytes. Ulinastatin, a glycoprotein purified from human urine, suppressed both the IL-1 production and the IL- 1 induced reduction of proteoglycan synthesis. In addition, ulinastatin inhibited superoxide generation. These actions of ulinastatin seemed to be related to its inhibitory actions against serine proteases such as trypsin, alpha-chymotrypsin, plasmin, leukocyte elastase and leukocyte cathepsin G. Triamcinolone suppressed the IL-1 production more potently than ulinastatin and it also suppressed the IL-1 induced reduction of proteoglycan synthesis. Triamcinolone alone, however, reduced the proteoglycan synthesis, and it did not affect the superoxide generation. In contrast, indomethacin had no effect on proteoglycan synthesis and superoxide generation, although it accelerated the IL-1 production. These results indicate that these three drugs have different mechanisms of action on the factors involved in the pathogenesis of osteoarthritis. Since ulinastatin has broad actions, which are considered to be beneficial for preventing some process of osteoarthritic pathogenesis, ulinastatin is expected to be an useful drug for the treatment of osteoarthritis.