Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
Autophagy activation by rapamycin reduces severity of experimental osteoarthritis.
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DOI：
10.1136/annrheumdis-2011-200557
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发表时间：
2012-04
影响因子：
27.4
通讯作者：
Lotz M
中科院分区：
文献类型：
--
作者：
Caramés B;Hasegawa A;Taniguchi N;Miyaki S;Blanco FJ;Lotz M
骨关节炎与关节软骨细胞死亡和细胞外基质降解有关。自噬是一种基本的细胞内稳态机制，在衰老和骨性关节炎软骨中被发现是不足的。这项研究确定了对哺乳动物靶标雷帕霉素(MTOR)的药理抑制是否在实验性骨性关节炎中具有疾病修改活性。切断2月龄C57BL/6小鼠胫骨内侧半月板韧带和内侧副韧带，建立实验性骨性关节炎动物模型(n=36)。分别给予雷帕霉素(1 mg/kg体重/d)(n=18)或二甲基亚砜(DMSO)载体对照组(n=18)，连续10周。采用半定量评分系统观察关节软骨和滑膜的组织病理学变化。免疫组织化学和免疫荧光染色分析雷帕霉素对mTOR信号转导、自噬、软骨动态平衡和炎症的影响。雷帕霉素影响小鼠膝关节mTOR信号通路，表现为抑制mTOR靶标核糖体蛋白S6的磷酸化和激活自噬的主要标志Lc3。与对照组相比，雷帕霉素组软骨退化的严重程度显著减轻(P<；0.01)，这与滑膜炎的显著减轻(P<；0.05)有关。雷帕霉素还能维持软骨细胞密度，降低关节软骨中ADAMTS-5和IL-1β的表达。这些结果表明，雷帕霉素至少部分通过自噬激活，可以减轻实验性骨关节炎的严重程度。药物激活自噬可能是治疗骨性关节炎的有效方法。
Osteoarthritis (OA) is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential cellular homeostasis mechanism that was found to be deficient in aging and OA cartilage. This study determined whether pharmacological inhibition of the mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has disease-modifying activity in experimental OA. Experimental OA was induced by transection of the medial meniscotibial ligament and the medial collateral ligament in 2-month old C57Bl/6 mice (n=36). Rapamycin (1 mg/kg weight/day) (n=18 mice) or DMSO vehicle control (n=18 mice) was administered intraperitoneally for 10 weeks. Histopathological changes in articular cartilage and synovium were examined by using semiquantitative scoring systems. Rapamycin effects on mTOR signaling, autophagy, cartilage homeostasis and inflammation were analyzed by immunohistochemistry and immunofluorescence staining. Rapamycin affected the mTOR signaling pathway in mouse knee joints as indicated by inhibition of ribosomal protein S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly (P < 0.01) reduced in the rapamycin treated group compared to the control group and this was associated with a significant (P < 0.05) decrease in synovitis. Rapamycin treatment also maintained cartilage cellularity, and decreased ADAMTS-5 and IL-1β expression in articular cartilage. These results suggest that rapamycin, at least in part by autophagy activation, reduces the severity of experimental OA. Pharmacological activation of autophagy may be an effective therapeutic approach for OA.
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影响因子：
37.8
作者：
Inuzuka, Yasutaka;Okuda, Junji;Shioi, Tetsuo
通讯作者：
Shioi, Tetsuo
影响因子：
2.8
作者：
Krenn, V;Morawietz, L;König, A
通讯作者：
König, A
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
3.3
作者：
Mizushima, N;Yamamoto, A;Ohsumi, Y
通讯作者：
Ohsumi, Y
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T