Blocking Jak/STAT signalling using tofacitinib inhibits angiogenesis in experimental arthritis.
Blocking Jak/STAT signalling using tofacitinib inhibits angiogenesis in experimental arthritis.
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DOI：
10.1186/s13075-021-02587-8
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发表时间：
2021-08-14
影响因子：
4.9
通讯作者：
Giacomelli R
中科院分区：
文献类型：
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作者：
Di Benedetto P;Ruscitti P;Berardicurti O;Panzera N;Grazia N;Di Vito Nolfi M;Di Francesco B;Navarini L;Maurizi A;Rucci N;Teti AM;Zazzeroni F;Guggino G;Ciccia F;Dolo V;Alesse E;Cipriani P;Giacomelli R
在类风湿性关节炎（RA），血管生成过程中，发生与血管翳形成，可能是一个治疗目标。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。在伦理批准后，在RA滑膜组织上评价JAK-1、JAK-3、STAT-1、STAT-3和VEGF表达。在体外，通过Matrigel、Boyden小室试验和ki 67基因表达，评估用20 ng/ml VEGF和/或1 μM托法替尼刺激的内皮细胞（EC）的管形成、迁移和增殖。在体内，32只小鼠接受胶原（胶原诱导的关节炎（CIA）），32只小鼠接受PBS（对照）。在第19天，将CIA和对照小鼠分组：16只小鼠接受溶媒，16只小鼠接受托法替尼。第35天，观察大鼠关节炎评分、足关节厚度及血清VEGF和Ang-2水平。RA患者滑膜组织中JAK-1、JAK-3、STAT-1、STAT-3和VEGF的表达均显著高于健康对照组。在体外，托法替尼抑制EC形成血管、增殖和迁移的能力。在体内，与不含托法替尼的CIA相比，托法替尼给药可防止关节炎评分、爪厚度、滑膜血管以及VEGF和Ang-2血清蓄积增加。我们探索了托法替尼的抗血管生成作用，报告了其在CIA模型中抑制体外EC血管生成机制和体内新滑膜血管形成的能力。这些结果表明，托法替尼在RA期间的治疗作用也可能与其抗血管生成活性有关。在线版本包含补充材料，可通过10.1186/s13075-021-02587-8获得。
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. The online version contains supplementary material available at 10.1186/s13075-021-02587-8.
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影响因子：
--
作者：
Ando S;Kawada JI;Watanabe T;Suzuki M;Sato Y;Torii Y;Asai M;Goshima F;Murata T;Shimizu N;Ito Y;Kimura H
通讯作者：
Kimura H
影响因子：
20.1
作者：
Asahara, T;Chen, DH;Isner, JM
通讯作者：
Isner, JM
影响因子：
11.5
作者：
Banerjee S;Biehl A;Gadina M;Hasni S;Schwartz DM
通讯作者：
Schwartz DM
JAK抑制剂tofacitinib抑制类风湿关节炎中的滑膜JAK1-STAT信号传导。
影响因子：
27.4
作者：
Boyle DL;Soma K;Hodge J;Kavanaugh A;Mandel D;Mease P;Shurmur R;Singhal AK;Wei N;Rosengren S;Kaplan I;Krishnaswami S;Luo Z;Bradley J;Firestein GS
通讯作者：
Firestein GS
影响因子：
27.4
作者：
Gao W;McGarry T;Orr C;McCormick J;Veale DJ;Fearon U
通讯作者：
Fearon U