The plasminogen activation system in rheumatoid arthritis

Abstract

Thrombin cleaves single-chain urokinase-type plasminogen activator (scu-PA) into a virtually inactive two-chain form (tcu-PA/T). Little is known about the physiological importance of tcu-PA/T. To examine the occurrence of tcu-PA/T in vivo, we developed a sensitive and specific bioimmunoassay (BIA) for the assessment of tcu-PA/T in human body fluids. In this BIA, urokinase antigen was immuno-immobilized in microtiter plates and treated with cathepsin C, a specific activator of tcu-PA/T, after which plasminogen activator activity was measured. The occurrence of tcu-PA/T was assessed in the plasma of healthy individuals and sepsis patients, and in the synovial fluid of rheumatoid arthritis patients. In addition, the concentrations of urokinase antigen and scu-PA were measured. In the plasma of the healthy individuals the concentration of tcu-PA/T was below the detection limit of 0.2 ng/ml. In the plasma of almost all sepsis patients tcu-PA/T was found (median value 0.4 ng/ml). In the synovial fluid of all rheumatoid arthritis patients tcu-PA/T could be measured (median value 5.4 ng/ml), and its concentration was about twofold higher than the concentration found for scu-PA. In this group tcu-PA/T contributed to about 47% (median value) of urokinase antigen. From these data we conclude that inactivation of scu-PA by thrombin can take place in vivo under pathological conditions which involve the production of thrombin. In this way thrombin may regulate fibrinolysis and extracellular proteolysis.