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

Renpeng Zhou; Yong Chen; Shufang Li; Xin Wei; Weirong Hu; Su'an Tang; Jie Ding; Wanjin Fu; Hailin Zhang; Fan Chen; Wenjuan Hao; Yi Lin; Rendi Zhu; Ke Wang; Lei Dong; Yingjie Zhao; Xiaowen Feng; Feihu Chen; Changhai Ding; Wei Hu

doi:10.1016/j.redox.2022.102411

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

Redox Biol. 2022 Sep:55:102411. doi: 10.1016/j.redox.2022.102411. Epub 2022 Jul 19.

Authors

Renpeng Zhou¹, Yong Chen², Shufang Li², Xin Wei³, Weirong Hu⁴, Su'an Tang⁵, Jie Ding², Wanjin Fu², Hailin Zhang⁶, Fan Chen⁶, Wenjuan Hao⁶, Yi Lin⁶, Rendi Zhu⁶, Ke Wang⁴, Lei Dong⁶, Yingjie Zhao¹, Xiaowen Feng⁴, Feihu Chen⁴, Changhai Ding⁷, Wei Hu⁸

Affiliations

¹ Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
² Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
³ The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, PR China.
⁴ The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
⁵ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁶ Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
⁷ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. Electronic address: Changhai.Ding@utas.edu.au.
⁸ Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China. Electronic address: huwei@ahmu.edu.cn.

Abstract

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.

Keywords: Ferroptosis; NOX4; PKCα; Rheumatoid arthritis; TRPM7.