Urokinase-mediated fibrinolysis in the synovial fluid of rheumatoid arthritis patients may be affected by the inactivation of single chain urokinase type plasminogen activator by thrombin.
BACKGROUND
Excessive fibrin deposition within the inflamed joints of rheumatoid arthritis (RA) patients suggests that local fibrinolysis is inefficient, which seems to be in contrast with the observed increased levels of urokinase type plasminogen activator (u-PA). Thrombin-mediated inactivation of single chain u-PA (scu-PA) into an inactive form called thrombin-cleaved two chain u-PA (tcu-PA/T) may provide a possible explanation for this contradiction.


OBJECTIVE
To assess the occurrence of tcu-PA/T in the synovial fluid of patients with RA and with osteoarthritis (OA), and in the synovial fluid of controls to find support for thrombin-mediated inactivation of scu-PA in RA.


METHODS
Levels of scu-PA and tcu-PA/T were measured in the synovial fluid of 20 RA patients, nine OA patients and 14 controls using sensitive bioimmunoassays. Total urokinase antigen was quantified by a urokinase ELISA.


RESULTS
tcu-PA/T was found in the synovial fluid of all RA and OA patients. Only in seven of 14 control samples, levels of tcu-PA/T could be measured above the detection limit of the assay (0.2 ng/ml). The concentrations of tcu-PA/T, scu-PA and u-PA:Ag were significantly higher in the synovial fluid of the RA and OA patients as compared with the controls, while the RA patients had significantly higher levels of tcu-PA/T and u-PA:Ag than the OA patients. In RA, tcu-PA/T seemed to account for more than 40% of total urokinase antigen, while the contribution of tcu-PA/T to total urokinase antigen was only minor in OA and the controls (9.0% and 6.6%, respectively).


CONCLUSIONS
A significant part of the high total urokinase antigen in the synovial fluid of RA patients can be attributed to tcu-PA/T, implying that a large amount of scu-PA is not available for fibrinolysis because of its inactivation by thrombin. Thus, thrombin may promote the inflammation process in RA by inhibiting the fibrinolytic system and preventing the removal of fibrin.
Braat
E A
EA
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.
Jie
A F
AF
Ronday
H K
HK
Beekman
B
B
Rijken
D C
DC
D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000503:physiopathology; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D010003:Osteoarthritis / Q000201:enzymology / Q000503:physiopathology; D013582:Synovial Fluid / Q000201:enzymology / Q000502:physiology; D013917:Thrombin / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator