T-2 toxin induces chondrocyte extracellular matrix degradation by regulating the METTL3-mediated Ctsk m6A modification

Bing Zhang; Haonan Li; Fang Qi; Qian Yu; Hong Jiang; Buyi Lin; Hexuan Dong; Hongzhi Li; Jun Yu

doi:10.1016/j.intimp.2024.113390

T-2 toxin induces chondrocyte extracellular matrix degradation by regulating the METTL3-mediated Ctsk m6A modification

Int Immunopharmacol. 2024 Oct 18;143(Pt 2):113390. doi: 10.1016/j.intimp.2024.113390. Online ahead of print.

Authors

Bing Zhang¹, Haonan Li², Fang Qi², Qian Yu², Hong Jiang², Buyi Lin², Hexuan Dong², Hongzhi Li³, Jun Yu⁴

Affiliations

¹ Institute for Kashin-Beck Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang, China; National Healthy Commission and Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Heilongjiang Provincial Laboratory of Trace Element and Human Health, Harbin Medical University, Harbin 150081, China; School of Public Health, Beihua University, Jilin 132013, Jilin, China.
² Institute for Kashin-Beck Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang, China; National Healthy Commission and Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Heilongjiang Provincial Laboratory of Trace Element and Human Health, Harbin Medical University, Harbin 150081, China.
³ School of Basic Medicine, Beihua University, Jilin 132013, Jilin, China. Electronic address: [email protected].
⁴ Institute for Kashin-Beck Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang, China; National Healthy Commission and Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Heilongjiang Provincial Laboratory of Trace Element and Human Health, Harbin Medical University, Harbin 150081, China. Electronic address: [email protected].

PMID: 39426235
DOI: 10.1016/j.intimp.2024.113390

Abstract

T-2 toxin is a major cause of Kashin-Beck disease (KBD), which is characterised by cartilage damage. N6-adenosine-methyltransferase-like 3 (METTL3) regulates cartilage injury; however, its role in T-2 toxin-induced cartilage injury remains elusive. Herein, we investigated the involvement of METTL3-mediated m6A modification in T-2 toxin-induced cartilage damage. METTL3-mediated m6A methylation levels were correlated with cartilage extracellular matrix (ECM) degradation, which was exacerbated following METTL3 silencing. Cathepsin K (Ctsk) was identified as a downstream target of METTL3 using m6A-methylated RNA immunoprecipitation（MeRIP）sequencing and RNA sequencing. Silencing Ctsk aggravated HT-2 toxin-induced ECM degradation. Increasing the m6A methylation levels in vivo via dietary methionine supplementation mitigated cartilage damage. In summary, HT-2 toxin induced cartilage ECM degradation by regulating the METTL3-mediated m6A modification of Ctsk. These findings highlight the METTL3/m6A/Ctsk axis as a potential therapeutic target for the treatment of KBD and other cartilage-associated diseases.

Keywords: Cartilage injury; Cathepsin K (Ctsk); Methyltransferase 3 (METTL3); T-2 toxin.