Urokinase plasminogen activator (uPA) has been widely studied for its role in physiological and diseased states. The broad proteolytic nature of uPA has been implicated in tissue remodeling in rheumatoid arthritis (RA). Previous studies in animal RA models have shown mixed evidence of the involvement of uPA in RA- in a model-dependent manner. Specifically, some clinical and pre-clinical work in mouse models of arthritis support an important role of uPA in RA. However, none of these have studied the activity or expression of uPA in RA and its correlation with the disease severity.
This study emphasizes on (a) establishing a rat model of collagen-induced arthritis (CIA) (which is relatively more relevant to human RA than its mouse counterpart), (b)evaluating the expression & activity of uPA in healthy and diseased rat CIA model system and (c) measuring any correlation of uPA activity/expression with that of the disease severity. Lastly, this study also investigates the in vivo efficacy of amiloride derived small molecule uPA inhibitor (BB2-30F) using the same rat CIA model system. The uPA activities, uPAR expression, and fibrinogen deposition in the joints in diseased animals were significantly higher than in non-arthritic control group and were moderately correlated with the disease severity.
Furthermore, future studies need to evaluate and optimize parameters for in vivo treatment of uPA inhibitors including the duration of its treatment and its efficacy in reducing RA signs & symptoms at the optimal dosage. Overall, the result of this study is likely to provide an insight into the potential pathophysiology of uPA and therapeutic potential of its inhibitors in RA.