During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA. After ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated. The expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib. We explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.

中文翻译：

---

使用托法替尼阻断 Jak/STAT 信号可抑制实验性关节炎的血管生成

在类风湿性关节炎 (RA) 期间，伴随血管翳形成发生的血管生成过程可能是治疗目标。JAK/STAT 通路可能发挥作用，这项工作的目的是研究 JAK 抑制剂托法替尼对 RA 期间发生的血管生成机制的抑制作用。伦理批准后，评估了 RA 滑膜组织上的 JAK-1、JAK-3、STAT-1、STAT-3 和 VEGF 表达。在体外，用 20 ng/ml VEGF 和/或 1 μM 托法替尼刺激的内皮细胞 (EC) 通过 Matrigel、Boyden 室测定和 ki67 基因表达评估管形成、迁移和增殖。在体内，32 只小鼠接受胶原蛋白（胶原诱导性关节炎 (CIA)）和 32 只小鼠 PBS（对照）。在第 19 天，CIA 和对照小鼠被分成：16 只接受载体的小鼠和 16 只接受托法替尼的小鼠。在第 35 天，评估关节炎评分、爪关节厚度和血清VEGF和Ang-2水平。RA患者滑膜组织中JAK-1、JAK-3、STAT-1、STAT-3和VEGF的表达明显高于健康对照组。在体外，托法替尼抑制 ECs 形成血管、增殖和迁移的能力。在体内，与不使用托法替尼的 CIA 相比，使用托法替尼可防止关节炎评分、爪厚度、滑膜血管以及 VEGF 和 Ang-2 血清积累的增加。我们探索了托法替尼的抗血管生成作用，报告了其在体外抑制 ECs 血管生成机制和体内新滑膜血管形成的能力，发生在 CIA 模型中。