Mammalian Target of Rapamycin Signaling Is Crucial for Joint Destruction in Experimental Arthritis and Is Activated in Osteoclasts From Patients With Rheumatoid Arthritis
Mammalian Target of Rapamycin Signaling Is Crucial for Joint Destruction in Experimental Arthritis and Is Activated in Osteoclasts From Patients With Rheumatoid Arthritis
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DOI：
10.1002/art.27504
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发表时间：
2010-08-01
影响因子：
--
通讯作者：
Schett, Georg
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文献类型：
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作者：
Cejka, Daniel;Hayer, Silvia;Schett, Georg
Objective.哺乳动物雷帕霉素靶蛋白（mTOR）通路的激活对于免疫细胞活化和骨代谢是重要的。迄今为止，mTOR信号传导对关节炎症和结构性骨和软骨损伤的贡献尚不清楚。本研究的目的是研究抑制mTOR作为炎性关节炎治疗的潜力。用2种不同的mTOR抑制剂西罗莫司或依维莫司治疗正在发展炎性关节炎的人肿瘤坏死因子转基因小鼠。研究了治疗对临床疾病活动、炎症以及局部关节和软骨破坏的影响。此外，在体外分析了mTOR抑制对破骨细胞存活和破骨细胞功能关键分子表达的影响。此外，类风湿性关节炎（RA）患者的滑膜组织进行了评估的mTOR通路的激活。西罗莫司或依维莫司抑制mTOR可减少滑膜破骨细胞形成，并防止局部骨侵蚀和软骨丢失。mTOR抑制后关节炎的临床体征改善，组织学评价显示滑膜炎减少。在体外，mTOR抑制下调消化酶的表达，并导致破骨细胞凋亡。此外，mTOR信号在类风湿关节炎患者滑膜中，特别是滑膜破骨细胞中表现出活性。通过mTOR的信号传导是炎症性关节炎中滑膜炎和结构损伤之间的重要联系。目前mTOR的药理学抑制剂可以有效保护关节免受结构损伤。
Objective. Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis.Methods. Human tumor necrosis factor-transgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway.Results. Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down-regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts.Conclusion. Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage.