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From the Arthritis and Inflammation Research Center, University ofMelbourne, Department of Medicine, Victoria, Australia
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-1ß 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-
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.
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