Arthritis and Inflammation Research Centre, Department of Medicine, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
Arthritis Res Ther. 2010;12(2):R37. doi: 10.1186/ar2946. Epub 2010 Mar 2.
Urokinase-type plasminogen activator (u-PA) has been implicated in fibrinolysis, cell migration, latent cytokine activation, cell activation, T-cell activation, and tissue remodeling, all of which are involved in the development of rheumatoid arthritis. Previously, u-PA has been reported to play a protective role in monoarticular arthritis models involving mBSA as the antigen, but a deleterious role in the systemic polyarticular collagen-induced arthritis (CIA) model. The aim of the current study is to determine how u-PA might be acting in systemic arthritis models.
The CIA model and bone marrow chimeras were used to determine the cellular source of u-PA required for the arthritis development. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitiative PCR and protein levels by ELISA. The requirement for u-PA in the type II collagen mAb-induced arthritis (CAIA) and K/BxN serum transfer arthritis models was determined using u-PA(-/-) mice. Neutrophilia was induced in the peritoneal cavity using either ovalbumin/anti-ovalbumin or the complement component C5a.
u-PA from a bone marrow-derived cell was required for the full development of CIA. The disease in u-PA(-/-) mice reconstituted with bone marrow from C57BL/6 mice was indistinguishable from that in C57BL/6 mice, in terms of clinical score, histologic features, and protein and gene expression of key mediators. u-PA(-/-) mice were resistant to both CAIA and K/BxN serum transfer arthritis development. u-PA(-/-) mice developed a reduced neutrophilia and chemokine production in the peritoneal cavity following ovalbumin/anti-ovalbumin injection; in contrast, the peritoneal neutrophilia in response to C5a was u-PA independent.
u-PA is required for the full development of systemic arthritis models involving immune complex formation and deposition. The cellular source of u-PA required for CIA is bone marrow derived and likely to be of myeloid origin. For immune complex-mediated peritonitis, and perhaps some other inflammatory responses, it is suggested that the u-PA involvement may be upstream of C5a signaling.
尿激酶型纤溶酶原激活物（u-PA）参与纤维蛋白溶解、细胞迁移、潜伏细胞因子激活、细胞激活、T 细胞激活和组织重塑，所有这些都与类风湿关节炎的发展有关。先前有报道称，u-PA 在涉及 mBSA 作为抗原的单关节炎模型中发挥保护作用，但在系统性多关节炎胶原诱导性关节炎（CIA）模型中发挥有害作用。本研究旨在确定 u-PA 在系统性关节炎模型中是如何发挥作用的。
使用 CIA 模型和骨髓嵌合体来确定关节炎发展所需的 u-PA 的细胞来源。通过定量 PCR 测量关节组织中炎症和破坏介质的基因表达，并通过 ELISA 测量蛋白水平。使用 u-PA(-/-) 小鼠确定 u-PA 在 II 型胶原单克隆抗体诱导的关节炎（CAIA）和 K/BxN 血清转移关节炎模型中的作用。通过卵清蛋白/抗卵清蛋白或补体成分 C5a 在腹腔内诱导中性粒细胞增多。
CIA 完全发展所需的 u-PA 来自骨髓来源的细胞。用来自 C57BL/6 小鼠的骨髓重建的 u-PA(-/-) 小鼠的疾病与 C57BL/6 小鼠的疾病在临床评分、组织学特征以及关键介质的蛋白和基因表达方面无法区分。u-PA(-/-) 小鼠对 CAIA 和 K/BxN 血清转移关节炎的发展均具有抗性。u-PA(-/-) 小鼠在卵清蛋白/抗卵清蛋白注射后腹腔内中性粒细胞增多和趋化因子产生减少；相反，对 C5a 的腹腔中性粒细胞增多与 u-PA 无关。
u-PA 是涉及免疫复合物形成和沉积的系统性关节炎模型完全发展所必需的。CIA 所需的 u-PA 细胞来源是骨髓来源的，可能来源于骨髓细胞。对于免疫复合物介导的腹膜炎，以及其他一些炎症反应，建议 u-PA 的参与可能发生在 C5a 信号的上游。
