TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis.
TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis.
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TRPM7 通道抑制通过抑制 PKCα-NOX4 轴来减轻类风湿性关节炎关节软骨细胞铁死亡
DOI：
10.1016/j.redox.2022.102411
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发表时间：
2022-09
期刊：
影响因子：
11.4
通讯作者：
Hu, Wei
中科院分区：
文献类型：
--
作者：
Zhou, Renpeng;Chen, Yong;Li, Shufang;Wei, Xin;Hu, Weirong;Tang, Suan;Ding, Jie;Fu, Wanjin;Zhang, Hailin;Chen, Fan;Hao, Wenjuan;Lin, Yi;Zhu, Rendi;Wang, Ke;Dong, Lei;Zhao, Yingjie;Feng, Xiaowen;Chen, Feihu;Ding, Changhai;Hu, Wei
类风湿性关节炎（RA）相关的关节软骨破坏中铁下垂的作用尚未确定。我们先前报道瞬时受体电位melastatin 7（TRPM 7）表达与RA软骨破坏相关。在此，我们进一步表征了TRPM 7在软骨细胞铁凋亡中的作用。发现TRPM 7的表达在源自佐剂性关节炎（AA）大鼠、人RA患者的关节软骨细胞和用铁凋亡诱导剂erastin处理的培养软骨细胞中升高。TRPM 7敲除或药理学抑制保护原代大鼠关节软骨细胞和人软骨细胞（C28/I2细胞）免于铁凋亡。此外，TRPM 7通道活性被证明有助于软骨细胞铁凋亡的细胞内Ca 2+的升高。从机制上讲，发现PKCα-NOX 4轴对erastin刺激产生反应，导致TRPM 7介导的软骨细胞铁凋亡。与此同时，PKCα直接与NOX 4结合，TRPM 7通道抑制可以减少这种结合。腺相关病毒9介导的TRPM 7沉默或用2-APB阻断TRPM 7可减轻AA大鼠关节软骨破坏，并抑制软骨细胞铁凋亡。总的来说，TRPM 7的遗传和药理学抑制通过PKCα-NOX 4轴减轻关节软骨损伤和软骨细胞铁凋亡，表明TRPM 7介导的软骨细胞铁凋亡是预防和治疗RA的有希望的靶点。铁凋亡首先在RA关节软骨细胞中发现，抑制软骨细胞铁凋亡保护关节软骨损伤。在RA关节软骨中确定了异常高水平的TRPM 7，以及TRPM 7对软骨细胞铁凋亡的调节。TRPM 7通道抑制剂2-氨基乙氧基二苯基硼酸酯（2-APB）可能是一种潜在的铁凋亡抑制剂。TRPM 7的抑制通过PKCα-NOX 4轴减弱RA关节软骨细胞铁凋亡，表明TRPM 7介导的软骨细胞铁凋亡是RA治疗的有希望的靶点。
A role for ferroptosis in articular cartilage destruction associated with rheumatoid arthritis (RA) has not been identified. We previously reported transient receptor potential melastatin 7 (TRPM7) expression was correlated with RA cartilage destruction. Herein, we further characterized a role for TRPM7 in chondrocyte ferroptosis. The expression of TRPM7 was found to be elevated in articular chondrocytes derived from adjuvant arthritis (AA) rats, human RA patients, and cultured chondrocytes treated with the ferroptosis inducer, erastin. TRPM7 knockdown or pharmacological inhibition protected primary rat articular chondrocytes and human chondrocytes (C28/I2 cells) from ferroptosis. Moreover, TRPM7 channel activity was demonstrated to contribute to chondrocyte ferroptosis by elevation of intracellular Ca2+. Mechanistically, the PKCα-NOX4 axis was found to respond to stimulation with erastin, which resulted in TRPM7-mediated chondrocyte ferroptosis. Meanwhile, PKCα was shown to directly bind to NOX4, which could be reduced by TRPM7 channel inhibition. Adeno-associated virus 9-mediated TRPM7 silencing or TRPM7 blockade with 2-APB alleviated articular cartilage destruction in AA rats and inhibited chondrocyte ferroptosis. Collectively, both genetic and pharmacological inhibitions of TRPM7 attenuated articular cartilage damage and chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for the prevention and treatment of RA. Ferroptosis was first identified in RA articular chondrocytes, and inhibition of chondrocyte ferroptosis protected articular cartilage damage. Abnormally high levels of TRPM7 were determined in RA articular cartilage, as well as TRPM7 regulation of chondrocyte ferroptosis. TRPM7 channel inhibitor 2-aminoethoxydiphenyl borate (2-APB) might be used as a potential potent ferroptosis inhibitor. Inhibition of TRPM7 attenuated RA articular chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for RA treatment.
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影响因子：
11.1
作者：
Miao Y;Chen Y;Xue F;Liu K;Zhu B;Gao J;Yin J;Zhang C;Li G
通讯作者：
Li G
影响因子：
3.7
作者：
Mateen S;Moin S;Khan AQ;Zafar A;Fatima N
通讯作者：
Fatima N
影响因子：
4
作者：
Bai, Qian;Shao, Jinping;Dong, Tieli
通讯作者：
Dong, Tieli
影响因子：
5
作者：
Gatica, Sebastian;Villegas, Vicente;Simon, Felipe
通讯作者：
Simon, Felipe
影响因子：
4.8
作者：
Li, Mingjiang;Du, Jianyang;Yue, Lixia
通讯作者：
Yue, Lixia