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Plasminogen activator inhibitor type-1 deficiency attenuates murine antigen-induced arthritis
K Van Ness1, V Chobaz-Péclat, M Castellucci
1Centre Hospitalier Universitaire Vaudois, Laboratoire de Rhumatologie, Nestlé 05-5029, 1011 Lausanne, Switzerland.
Objective:
To examine the role of plasminogen activator inhibitor type-1 (PAI-1), the major fibrinolytic inhibitor, in vivo during murine antigen-induced arthritis (AIA).
Methods:
AIA was induced in PAI-1-deficient mice and control wild-type mice. Arthritis severity was evaluated by technetium 99m (99mTc) uptake in the knee joints and by histological scoring. Intra-articular fibrin deposition was examined by immunohistochemistry and synovial fibrinolysis quantitated by tissue D-dimer measurements and zymograms.
Results:
Joint inflammation, quantitated by 99mTc uptake, was significantly reduced in PAI-1(-/-) mice on day 7 after arthritis onset (P<0.01). Likewise, synovial inflammation, evaluated by histological scoring, was significantly decreased in PAI-1-deficient mice on day 10 after arthritis onset (P<0.001). Articular cartilage damage was significantly decreased in PAI-1(-/-) mice, as shown by histological grading of safranin-O staining on day 10 after arthritis onset (P<0.005). Significantly decreased synovial accumulation of fibrin was observed by day 10 in arthritic joints of PAI-1(-/-) mice (P<0.005). Accordingly, the synovial tissue content of D-dimers, the specific fibrin degradation products generated by plasmin, were increased in PAI-1(-/-) mice (P<0.02). Finally, as expected, PA activity was increased in synovial tissues from PAI-1(-/-) mice, as shown by zymographic analysis.
Conclusions:
These results indicate that deficiency of PAI-1 results in increased synovial fibrinolysis, leading to reduced fibrin accumulation in arthritic joints and reduced severity of AIA.
