Role of plasminogen activator inhibitor – 1 (PAI-1) in regulating the pathogenesis of S. aureus arthritis via plasminogen pathway

Abstract

uPA/tPA-mediated activation of plasminogen/plasmin pathway during S. aureus arthritis facilitates the invasion of phagocytes in the affected joint, induces production of cytokines and triggers inflammatory pathways. PAI-1, an effective inhibitor of both uPA and tPA, attenuates plasmin activity. Hence, the objective of our study was to evaluate the effect of exogenously administered PAI-1 on uPA/tPA-mediated activation of plasminogen/plasmin and its impact on the progression of arthritis. The mice were infected with live S. aureus and treated with PAI-1. Mice were sacrificed at 3, 9 and 15 days post infection and thereafter assessment of parameters related to arthritic destruction was done. PAI-1 administration resulted into decrement in uPA and tPA activities with a concomitant reduction in plasmin and MMP-2. A significant decrement in the joint and paw swelling with lower levels of inflammatory cytokines, RANKL and OPN activities were detected in case of early PAI-1 treatment. This study suggests administration of PAI-1 during S.aureus arthritis reduces the severity of arthritis by ameliorating uPA and plasmin-induced inflammatory responses and subsequent arthritic destruction.