TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis

• Published in: Redox biology Vol. 55; p. 102411
• Main Authors: Zhou, Renpeng, Chen, Yong, Li, Shufang, Wei, Xin, Hu, Weirong, Tang, Su'an, 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
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2022; Elsevier
• Subjects: Ferroptosis; NOX4; PKCα; Research Paper; Rheumatoid arthritis; TRPM7; Ferroptosis; NOX4; TRPM7; PKCα; Rheumatoid arthritis
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102411

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. [Display omitted] •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.