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

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 2), p.113390, Article 113390
• Main Authors: Zhang, Bing, Li, Haonan, Qi, Fang, Yu, Qian, Jiang, Hong, Lin, Buyi, Dong, Hexuan, Li, Hongzhi, Yu, Jun
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Cartilage injury; Cathepsin K (Ctsk); Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - metabolism; Extracellular Matrix - metabolism; Humans; Male; Methylation; Methyltransferase 3 (METTL3); Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Inbred C57BL; T-2 toxin; T-2 Toxin - toxicity
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113390

[Display omitted] •T-2 toxin exposure reduces METTL3-mediated m6A modification.•Silencing METTL3 intensifies toxin-induced ECM degradation.•HT-2 toxin regulates ECM via METTL3-mediated Ctsk m6A modification.•Methionine supplementation mitigates T-2 toxin-induced cartilage damage.•METTL3-Ctsk m6A modification plays a key role in cartilage injury. 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.