Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis.
The plasminogen activators, urokinase PA (u-PA) and tissue-type PA (t-PA), are believed to play important roles in inflammatory cell infiltration, fibrin deposition, and joint destruction associated with rheumatoid arthritis; however, their precise roles in such processes, particularly u-PA, have yet to be defined. Using gene-deficient mice we examined the relative contribution of the PAs to the chronic systemic collagen-induced arthritis model. Based on clinical and histological assessments, u-PA-/- mice developed significantly milder disease and t-PA-/- mice more severe disease compared with the relevant wild-type mice. Fibrin deposition within joints paralleled disease severity and was particularly pronounced in t-PA-/- mice. Likewise, cytokine levels in the synovium reflected the severity of disease, with interleukin-1beta levels in particular being lower in u-PA-/- mice and increased in t-PA-/- mice. The antibody response to type II collagen was normal in both knockouts; however, T cells from u-PA-/- mice had a reduced proliferative response and produced less interferon-gamma on antigen stimulation in vitro. These results indicate that the major effect of u-PA in the collagen-induced arthritis model is deleterious, whereas that of t-PA is protective. Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis.
Cook
Andrew D
AD
Arthritis and Inflammation Research Center, University of Melbourne, Department of Medicine, Victoria, Australia. adcook@unimelb.edu.au
Braine
Emma L
EL
Campbell
Ian K
IK
Hamilton
John A
JA
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005337:Fibrin / Q000378:metabolism; D007150:Immunohistochemistry; D007596:Joints / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010959:Tissue Plasminogen Activator / Q000172:deficiency* / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics
D005337:Fibrin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator