Multi-Organ Transplant Program, University of Toronto and Toronto General Hospital, Toronto, ON, Canada.
Scand J Rheumatol. 2011;40(4):269-78. doi: 10.3109/03009742.2010.536163. Epub 2011 Apr 6.
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.
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).
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.
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.
纤维蛋白沉积是胶原诱导关节炎（CIA）发病机制的重要组成部分，CIA 是类风湿关节炎（RA）的实验模型。膜相关纤维蛋白原样蛋白 2（mFGL2）是一种新型诱导性凝血酶原酶，通过替代途径生成纤维蛋白，并已报道参与多种免疫介导性疾病的发病机制。我们假设炎症滑膜中 mFGL2 的表达有助于关节炎中纤维蛋白沉积和随后的炎症。
DBA/1 小鼠用 100μg 牛型 II 胶原（CII）乳化于完全弗氏佐剂（CFA）中免疫，随后注射脂多糖（LPS）。在 CIA 诱导后，检查 CIA 小鼠和 CD200 治疗小鼠中 mFGL2 与纤维蛋白沉积相关的表达。为了直接评估 mFGL2 的贡献，用抗 CII 抗体注射 fgl2(-/-) 小鼠。
在发生 CIA 的小鼠关节中，fgl2 mRNA 转录物和 mFGL2 蛋白水平显著上调。纤维蛋白沉积在滑膜衬里和关节腔内明显，与 mFGL2 的表达相关。免疫抑制剂 CD200 抑制 CIA 与 fgl2 mRNA 和 mFGL2 蛋白表达降低以及纤维蛋白沉积缺失相关。注射抗 CII 后，所有 fgl2(+/+) 小鼠均出现严重关节炎，具有 RA 的临床和组织学表现特征，而 fgl2(-/-) 小鼠未出现任何关节炎的临床或组织学表现。
本研究表明 mFGL2 的凝血酶原酶活性有助于实验性关节炎的发病机制。这些研究可能对 RA 患者具有治疗意义。
