Exacerbation of antigen-induced arthritis in urokinase-deficient mice.

Abstract

In rheumatoid arthritis, synovial expression of urokinase (uPA) activity is greatly increased (Busso, N., V. Péclat, A. So, and A.-P. Sappino. 1997. Ann. Rheum. Dis. 56:550-557). We report the same effect in murine antigen-induced arthritis. uPA-mediated plasminogen activation in arthritic joints may have deleterious effects via degradation of cartilage and bone matrix proteins as well as beneficial effects via fibrin degradation. We evaluated these contrasting effects in vivo by analyzing the phenotype of uPA-deficient (uPA Ϫ / Ϫ ) and control mice during antigen-induced arthritis.Joint inflammation was comparable in both groups up to day 3 and subsequently declined in control mice, remaining significantly elevated in uPA Ϫ / Ϫ mice on days 10 and 30 after arthritis onset. Likewise, synovial thickness was markedly increased in uPA-deficient mice persisting for up to 2 mo, whereas it subsided in control animals. Bone erosion was exacerbated in uPA Ϫ / Ϫ mice on day 30. By contrast, no difference in articular cartilage proteoglycan content was found between both groups. Significantly increased accumulation of fibrin was observed by day 30 in arthritic joints of uPA Ϫ / Ϫ mice. We hypothesized that synovial fibrin deposition plays a role in joint inflammation. Accordingly, defibrinogenation of uPA Ϫ / Ϫ mice by ancrod significantly decreased the sustained joint inflammation. All the above observations were reproducible in plasminogen-deficient (Pln Ϫ / Ϫ ) mice.In conclusion, synovial fibrin deposition plays a role as a nonimmunological mechanism which sustains chronic arthritis. ( J. Clin. Invest. 1998. 102:41-50.)

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

“…In both of these studies with tPA Ϫ/Ϫ mice, there was a dramatic increase in fibrin deposition in the joint, which appeared to correlate with disease severity. Such an increase in fibrin deposition was also noted in the uPA Ϫ/Ϫ mouse model in which AIA was exacerbated (7).…”

Evaluation of protease‐activated receptor 2 in murine models of arthritis

“…For AIA, mice were immunized as described elsewhere (13). Arthritis was induced on day 21 by intraarticular injection of 100 g of methylated bovine serum albumin (mBSA) in 10 l of sterile phosphate buffered saline (PBS) into the right knee; the left knee was injected with sterile PBS alone.…”

“…Arthritis was induced on day 21 by intraarticular injection of 100 g of methylated bovine serum albumin (mBSA) in 10 l of sterile phosphate buffered saline (PBS) into the right knee; the left knee was injected with sterile PBS alone. Arthritis was assessed by measuring technetium uptake as described previously (13).…”

“…Tissues and sections were prepared as described previously (13). Each section was graded independently by 2 observers who were unaware of the animal's genotype.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…In some models, deletion of uPA, plasminogen, or tPA exacerbated arthritis, with increased fibrin accumulation in the joint (31,33), while uPA or plasminogen deletion in other models resulted in only mild disease (31,34,35). The reasons for such conflicting observations are unknown, but the differences may be partly attributable to the different pathologies reported in the models used (32).…”