Busso N, Péclat V, Van Ness K, Kolodziesczyk E, Degen J, Bugge T, So A
Centre Hospitalier Universitaire Vaudois, Laboratoire de Rhumatologie, 1011 Lausanne, Switzerland.
J Clin Invest. 1998 Jul 1;102(1):41-50. doi: 10.1172/JCI2312.
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-/-) 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-/- 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-/- 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-/- mice. We hypothesized that synovial fibrin deposition plays a role in joint inflammation. Accordingly, defibrinogenation of uPA-/- mice by ancrod significantly decreased the sustained joint inflammation. All the above observations were reproducible in plasminogen-deficient (Pln-/-) mice. In conclusion, synovial fibrin deposition plays a role as a nonimmunological mechanism which sustains chronic arthritis.
在类风湿性关节炎中，尿激酶（uPA）活性的滑膜表达显著增加（Busso, N., V. Péclat, A. So, and A. -P. Sappino. 1997. Ann. Rheum. Dis. 56:550-557）。我们报道在小鼠抗原诱导的关节炎中也有同样的效应。关节炎关节中uPA介导的纤溶酶原激活可能通过降解软骨和骨基质蛋白产生有害作用，同时也可能通过纤维蛋白降解产生有益作用。我们通过分析抗原诱导关节炎期间uPA缺陷（uPA-/-）小鼠和对照小鼠的表型，在体内评估了这些相反的作用。在第3天之前，两组的关节炎症相当，随后对照小鼠的炎症下降，而在关节炎发作后第10天和第30天，uPA-/-小鼠的炎症仍显著升高。同样，uPA缺陷小鼠的滑膜厚度在长达2个月的时间内显著增加，而对照动物的滑膜厚度则消退。在第30天，uPA-/-小鼠的骨侵蚀加剧。相比之下，两组之间的关节软骨蛋白聚糖含量没有差异。在uPA-/-小鼠的关节炎关节中，到第30天时观察到纤维蛋白的积累显著增加。我们推测滑膜纤维蛋白沉积在关节炎症中起作用。因此，用安克洛酶使uPA-/-小鼠去纤维蛋白原化可显著降低持续的关节炎症。所有上述观察结果在纤溶酶原缺陷（Pln-/-）小鼠中均可重现。总之，滑膜纤维蛋白沉积作为一种非免疫机制在维持慢性关节炎中起作用。
