State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China.
Cell Rep. 2024 Aug 27;43(8):114535. doi: 10.1016/j.celrep.2024.114535. Epub 2024 Jul 31.
Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (mA), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that mA affects the progression of osteoarthritis, its function in the development and homeostasis of articular cartilage remains unclear. Here we report that Mettl3 deficiency in chondrocytes leads to mandibular condylar cartilage morphological alterations, early temporomandibular joint osteoarthritis, and diminished adaptive response to abnormal mechanical stimuli. Mechanistically, METTL3 modulates Lats1 mRNA methylation and facilitates its degradation in an mA-YTHDF2-dependent manner, which subsequently influences the degradation and nuclear translocation of YAP1. Intervention with the Hippo pathway inhibitor XMU-MP-1 alleviates condylar abnormality caused by Mettl3 knockout. Our findings demonstrate the role of METTL3 in cartilage development and homeostasis, offering insights into potential treatment strategies for osteoarthritis.
软骨维持关节的结构和功能，其功能紊乱会导致潜在的骨关节炎。N6-甲基腺苷（m6A）是真核生物中最广泛的转录后修饰，在调节生物过程中起着关键作用。虽然目前的研究表明 m6A 会影响骨关节炎的进展，但它在关节软骨的发育和稳态中的功能尚不清楚。在这里，我们报道了软骨细胞中 Mettl3 的缺失会导致下颌髁突软骨形态改变、早发性颞下颌关节骨关节炎以及对异常机械刺激的适应性反应减弱。在机制上，METTL3 调节 Lats1 mRNA 的甲基化，并以 m6A-YTHDF2 依赖的方式促进其降解，从而影响 YAP1 的降解和核转位。Hippo 通路抑制剂 XMU-MP-1 的干预减轻了 Mettl3 敲除引起的髁突异常。我们的研究结果表明 METTL3 在软骨发育和稳态中的作用，为骨关节炎的潜在治疗策略提供了新的见解。
