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通过FTO介导的SMAD2 m6A修饰可以保护软骨免受骨关节炎的侵害

Hongyi Zhou^1,2, Ziang Xie^1,2, Yu Qian³

¹Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Experimental & molecular medicine

|October 3, 2024

概括

N6-甲基氨酸 (m6A) 修饰增加了骨关节炎 (OA) 软骨. 减少脂肪质量和与肥胖相关的蛋白质 (FTO) 脱甲基酶加速了OA,这表明FTO激活是潜在的OA疗法.

科学领域:

表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
分子生物学分子生物学
生物化学生物化学

背景情况:

N6-甲基氨酸 (m6A) 是一种普遍存在的表观遗传修饰,与退行性疾病有关.
在骨关节炎 (OA) 发病过程中m6A的具体作用仍然不完全理解.
骨关节炎是关节退化和残疾的主要原因.

研究的目的:

研究m6A修饰在人类骨关节炎 (OA) 软骨中的作用和机制.
为了确定关键的m6A相关的酶参与OA发展.
根据m6A规则,探索OA的潜在治疗点.

主要方法:

对人类OA软骨和软骨细胞中m6A修饰水平的分析.
对m6A修饰酶的定量评估,特别是FTO (脂肪质量和与肥胖相关的蛋白质).
在冠状细胞中条件淘汰FTO以评估其对OA进展的影响.
通过YTHDF2 (YTH N6-甲基氨酸RNA结合蛋白F2) 调查RUNX1 (Runt相关转录因子-1) 对FTO调节及其对SMAD2mRNA稳定性的下游影响.

主要成果:

在人体OA软骨和退化的肌体细胞中,m6A修饰水平显著增加.
在OA中,m6A脱甲基酶FTO的表达显著下降.
条件淘汰FTO加剧了OA的进展.
FTO转录由RUNX1.1.进行调节.
减少FTO导致SMAD2mRNA上的m6A增加,通过YTHDF2招募降低其稳定性.

结论:

该研究阐明了一种涉及FTO,RUNX1,m6A修饰和SMAD2在OA进展中的新机制.
减少FTO表达和随后增加的m6A修饰有助于OA的发病.
激活FTO以减少m6A修饰并增强SMAD2稳定性,为骨关节炎提供了一个潜在的治疗策略.

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