Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis.
Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis.
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DOI：
10.1016/j.freeradbiomed.2018.01.013
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发表时间：
2018-02-20
影响因子：
7.4
通讯作者：
Haqqi TM
中科院分区：
文献类型：
--
作者：
Khan NM;Ahmad I;Haqqi TM
Nrf 2是一种氧化还原调节的转录因子，最近已被证明在软骨完整性中发挥作用，但其机制在很大程度上仍然未知。骨关节炎（OA）是一种多因素的疾病，其中发生局灶性软骨退化。在此，我们研究了Nrf 2是否通过抑制IL-1β刺激的人OA软骨细胞中的氧化应激和凋亡来发挥软骨保护作用。与正常软骨相比，Nrf 2及其靶基因HO-1、NQO 1和SOD 2在OA软骨中的表达显著升高，并且与同一患者OA软骨的光滑区域相比，受损区域中的Nrf 2及其靶基因HO-1、NQO 1和SOD 2的表达也较高。用IL-1β处理的人软骨细胞导致稳健的Nrf 2/ARE报告基因活性，其被抗氧化剂预处理抑制，表明Nrf 2活性是由于IL-1β诱导的ROS产生。Nrf 2的异位表达显著抑制了IL-1β诱导的ROS的产生，而Nrf 2敲低显著增加了OA软骨细胞中基础和IL-1β诱导的ROS水平。此外，Nrf 2激活显著抑制了IL-1β诱导的外源性和内源性凋亡途径的激活，如通过抑制OA软骨细胞中的DNA片段化、Caspase-3、Caspase-8、Caspase-9的激活、PARP的裂解、细胞色素-c的释放、线粒体功能障碍和线粒体ROS产生所确定的。Nrf 2在OA软骨细胞中的过表达增加了抗凋亡蛋白的表达，而促凋亡蛋白的表达被抑制。重要的是，Nrf 2过表达激活ERK 1/2及其下游靶点ELK 1、P70 S6 K和P90 RSK，并抑制IL-1β诱导的OA软骨细胞凋亡，而抑制ERK 1/2激活则取消了Nrf 2对OA软骨细胞的保护作用。综上所述，我们的数据表明，Nrf 2是OA软骨细胞中具有抗氧化和抗凋亡功能的应激反应蛋白，并通过激活ERK 1/2/ELK 1-P70 S6 K-P90 RSK信号轴发挥作用。Nrf 2的这些活性使其成为开发用于管理OA的新疗法的有希望的候选者。
Nrf2, a redox regulated transcription factor, has recently been shown to play a role in cartilage integrity but the mechanism remains largely unknown. Osteoarthritis (OA) is a multifactorial disease in which focal degradation of cartilage occurs. Here, we studied whether Nrf2 exerts chondroprotective effects by suppressing the oxidative stress and apoptosis in IL-1β stimulated human OA chondrocytes. Expression of Nrf2 and its target genes HO-1, NQO1 and SOD2 was significantly high in OA cartilage compared to normal cartilage and was also higher in damaged area compared to smooth area of OA cartilage of the same patient. Human chondrocytes treated with IL-1β resulted in robust Nrf2/ARE reporter activity, which was inhibited by pretreatment with antioxidants indicating that Nrf2 activity was due to IL-1β-induced ROS generation. Ectopic expression of Nrf2 significantly suppressed the IL-1β-induced generation of ROS while Nrf2 knockdown significantly increased the basal as well as IL-1β-induced ROS levels in OA chondrocytes. Further, Nrf2 activation significantly inhibited the IL-1β-induced activation of extrinsic and intrinsic apoptotic pathways as determined by inhibition of DNA fragmentation, activation of Caspase-3,-8,-9, cleavage of PARP, release of cytochrome-c, suppression of mitochondrial dysfunction and mitochondrial ROS production in OA chondrocytes. Nrf2 over-expression in OA chondrocytes increased the expression of anti-apoptotic proteins while pro-apoptotic proteins were suppressed. Importantly, Nrf2 over-expression activated ERK1/2 and its downstream targets-ELK1, P70S6K and P90RSK and suppressed the IL-1β-induced apoptosis whereas inhibition of ERK1/2 activation abrogated the protective effects of Nrf2 in OA chondrocytes. Taken together, our data demonstrate that Nrf2 is a stress response protein in OA chondrocytes with anti-oxidative and anti-apoptotic function and acts via activation of ERK1/2/ELK1-P70S6K-P90RSK signaling axis. These activities of Nrf2 make it a promising candidate for the development of novel therapies for the management of OA.
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DOI：
10.1016/j.clim.2012.12.011
发表时间：
2013-03
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Haseeb A;Haqqi TM
通讯作者：
Haqqi TM
组蛋白脱乙酰酶抑制激活 Nrf2 并预防骨关节炎
影响因子：
4.9
作者：
Cai D;Yin S;Yang J;Jiang Q;Cao W
通讯作者：
Cao W
影响因子：
4
作者：
Abusarah, Jamilah;Benabdoune, Houda;Benderdour, Mohamed
通讯作者：
Benderdour, Mohamed
影响因子：
6.2
作者：
Danilov, Camelia A.;Chandirasekaran, Krish;Racz, Jennifer;Soane, Lucian;Zielke, Carol;Fiskum, Gary
通讯作者：
Fiskum, Gary
影响因子：
4
作者：
Hosseinzadeh, Azam;Jafari, Davood;Sharifi, Ali M.
通讯作者：
Sharifi, Ali M.