The prothrombinase activity of FGL2 contributes to the pathogenesis of experimental arthritis

Abstract

Objective: Fibrin deposition is integral to the pathogenesis of collagen-induced arthritis (CIA), an experimental model of rheumatoid arthritis (RA). Membrane-associated fibrinogen-like protein 2 (mFGL2), a novel inducible prothrombinase, generates fibrin by an alternate pathway and has been reported to be involved in the pathogenesis of a number of immune-mediated diseases. We hypothesized that expression of mFGL2 in inflamed synovium contributes to the fibrin deposition and subsequent inflammation in arthritis.

Methods: DBA/1 mice were immunized with 100 µg bovine collagen type II (CII) emulsified in complete Freund's adjuvant (CFA) followed by lipopolysaccharide (LPS) injection. Expression of mFGL2 prothrombinase in association with fibrin deposition was examined in mice with CIA and CD200-treated mice following induction of CIA. To directly assess the contribution of mFGL2, fgl2^−/− mice were injected with antibody to CII (anti-CII).

Results: Levels of fgl2 mRNA transcripts and mFGL2 protein were markedly up-regulated in joints of mice that developed CIA. Fibrin deposition was prominent within the synovial lining and articular joint space associated with expression of mFGL2. Inhibition of CIA by the immunosuppressant CD200 was associated with decreased expression of fgl2 mRNA and mFGL2 protein and absence of fibrin deposition. Following injection of anti-CII, all fgl2^+/+ mice developed severe arthritis with clinical and histological manifestations characteristic of RA, whereas fgl2^−/− mice failed to develop any clinical manifestation or histological evidence of arthritis.

Conclusions: This study demonstrates that the prothrombinase activity of mFGL2 contributes to the pathogenesis of experimental arthritis. These studies may have therapeutic implications for patients with RA.

Acknowledgements

We are grateful to Charmaine Beal for the preparation of this manuscript. This work was supported in part by grants from the Heart and Stroke Foundation of Canada (T5686) and the Canadian Institutes for Health Research (GR13298, 79561, and STP 53882).