The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis.
The plasminogen activator (PA) system has been proposed to have important roles in rheumatoid arthritis. Here we have used the autoimmune collagen type II (CII)-induced arthritis (CIA) model and mice deficient for urokinase-type PA (uPA) or plasminogen to investigate the role of the PA system for development of arthritis. Our data revealed that uPA-deficient mice have a lower severity and incidence of CIA than wild-type mice. Furthermore, although >80% of wild-type control mice developed CIA, we found that none of the 50 plasminogen-deficient littermates that were tested developed CIA within a 40-day period. Antibody generation after CII immunization as well as the binding of labeled anti-CII antibodies to the surface of cartilage were similar in wild-type and plasminogen-deficient mice. No sign of inflammation was seen when plasminogen-deficient mice were injected with a mixture of monoclonal antibodies against CII. However, after daily injections of human plasminogen, these mice developed arthritis within 5 days. Our finding that infiltration of inflammatory cells into the synovial joints was impaired in plasminogen-deficient mice suggests that uPA and plasminogen are important mediators of joint inflammation. Active plasmin is therefore essential for the induction of pathological inflammatory joint destruction in CIA.
Li
Jinan
J
Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden.
Ny
Annelii
A
Leonardsson
Göran
G
Nandakumar
Kutty Selva
KS
Holmdahl
Rikard
R
Ny
Tor
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001168:Arthritis / Q000276:immunology* / Q000473:pathology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005341:Fibrinolysin / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007596:Joints / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010958:Plasminogen / Q000378:metabolism* / Q000502:physiology*; D010960:Plasminogen Activators / Q000378:metabolism*; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D000939:Epitopes; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator
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