Plasminogen activator inhibitor type-1 deficiency attenuates murine antigen-induced arthritis.
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.
Van Ness
K
K
Centre Hospitalier Universitaire Vaudois, Laboratoire de Rhumatologie, Nestlé 05-5029, 1011 Lausanne, Switzerland.
Chobaz-Péclat
V
V
Castellucci
M
M
So
A
A
Busso
N
N
D000818:Animals; D000941:Antigens / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000276:immunology; D007719:Knee Joint / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013667:Technetium / Q000493:pharmacokinetics
D000941:Antigens; D017395:Plasminogen Activator Inhibitor 1; D013667:Technetium; D005337:Fibrin