EXACERBATION OF ANTIGEN-INDUCED ARTHRITIS IN UROKINASE-DEFICIENT MICE

In rheumatoid arthritis, synovial expression of urokinase (uPA) activi ty is greatly increased (Busso, N., V. Peclat, A. So, and A.-P. Sappin o, 1997. Ann. Rheum. Dis, 56:550-557), We report the same effect in mu rine antigen-induced arthritis, uPA-mediated plasminogen activation in arthritic joints may have deleterious effects via degradation of cart ilage and bone matrix proteins as well as beneficial effects via fibri n degradation. We evaluated these contrasting effects in vivo by analy zing the phenotype of uPA-deficient (uPA(-/-)) and control mice during antigen-induced arthritis. Joint inflammation was comparable in both groups up to day 3 and subsequently declined in control mice, remainin g significantly elevated in uPA(-/-) mice on days 10 and 30 after arth ritis onset. Likewise, synovial thickness was markedly increased in uP A-deficient mice persisting for up to 2 mo, whereas it subsided in con trol animals. Bone erosion was exacerbated in uPA(-/-) mice on day 30. By contrast, no difference in articular cartilage proteoglycan conten t was found between both groups. Significantly increased accumulation of fibrin was observed by day 30 in arthritic joints of uPA(-/-) mice. We hypothesized that synovial fibrin deposition plays a role in joint inflammation. Accordingly, defibrinogenation of uPA(-/-) mice by ancr od significantly decreased the sustained joint inflammation. All the a bove observations were reproducible in plasminogen-deficient (Pln(-/-) ) mice. In conclusion, synovial fibrin deposition plays a role as a no nimmunological mechanism which sustains chronic arthritis.