Stat3 as a potential therapeutic target for rheumatoid arthritis.
Stat3 as a potential therapeutic target for rheumatoid arthritis.
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DOI：
10.1038/s41598-017-11233-w
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发表时间：
2017-09-08
影响因子：
4.6
通讯作者：
Miyamoto T
中科院分区：
文献类型：
--
作者：
Oike T;Sato Y;Kobayashi T;Miyamoto K;Nakamura S;Kaneko Y;Kobayashi S;Harato K;Saya H;Matsumoto M;Nakamura M;Niki Y;Miyamoto T
类风湿性关节炎（RA）是一种多因素疾病，以慢性炎症和多关节破坏为特征。迄今为止，各种生物治疗类风湿性关节炎如抗肿瘤坏死因子α抗体已开发；然而，RA发展的机制尚不清楚，针对这种情况的靶向治疗尚未建立。在这里，我们提供证据表明信号换能器和转录激活因子3 （Stat3）促进关节炎小鼠模型的炎症和关节侵蚀。Stat3全局KO小鼠表现出早期胚胎致死性；因此，我们产生了有活力的Stat3条件敲除成年小鼠，并发现与对照组相比，它们对胶原诱导的关节炎（CIA）（最常见的RA模型）具有显著的抵抗力。然后我们使用体外培养系统筛选96种现有药物来选择Stat3抑制剂，并选择了5种候选抑制剂。其中3种药物能显著抑制CIA野生型小鼠关节炎和关节糜烂的发生。这些发现表明Stat3抑制剂可能作为RA治疗的有希望的药物。
Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen-induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild-type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy.
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