Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
Exp Mol Med. 2024 Oct;56(10):2283-2295. doi: 10.1038/s12276-024-01330-y. Epub 2024 Oct 3.
N6-methyladenosine (m6A) modification is one of the most prevalent forms of epigenetic modification and plays an important role in the development of degenerative diseases such as osteoarthritis (OA). However, the evidence concerning the role of m6A modification in OA is insufficient. Here, m6A modification was increased in human OA cartilage and degenerated chondrocytes. Among all of the m6A enzymes, the expression of the demethylase fat mass and obesity-associated protein (FTO) decreased dramatically. Conditional knockout of FTO in chondrocytes accelerates OA progression. FTO transcription is regulated by runt-related transcription factor-1 (RUNX1). Reduced FTO elevates m6A modification at the adenosine N6 position in SMAD family member 2 (SMAD2) mRNA, whose stability is subsequently modulated by the recruited m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2). Collectively, these findings reveal the function and mechanism of the m6A family member FTO in OA progression. Therefore, reducing m6A modification to increase SMAD2 stability by activating FTO might be a potential therapeutic strategy for OA treatment.
N6-甲基腺苷（m6A）修饰是最普遍的表观遗传修饰形式之一，在退行性疾病（如骨关节炎（OA））的发展中起着重要作用。然而，关于 m6A 修饰在 OA 中的作用的证据还不足。在这里，m6A 修饰在人类 OA 软骨和退化的软骨细胞中增加。在所有的 m6A 酶中，去甲基酶脂肪量和肥胖相关蛋白（FTO）的表达显著降低。软骨细胞中 FTO 的条件性敲除加速了 OA 的进展。FTO 的转录受 runt 相关转录因子-1（RUNX1）调控。FTO 减少导致 SMAD 家族成员 2（SMAD2）mRNA 中腺苷 N6 位的 m6A 修饰增加，随后由募集的 m6A 阅读蛋白 YTH N6-甲基腺苷 RNA 结合蛋白 F2（YTHDF2）调节其稳定性。总的来说，这些发现揭示了 m6A 家族成员 FTO 在 OA 进展中的功能和机制。因此，通过激活 FTO 降低 m6A 修饰以增加 SMAD2 稳定性可能是 OA 治疗的一种潜在治疗策略。
