METTL3 regulates cartilage development and homeostasis by affecting Lats1 mRNA stability in an m6A-YTHDF2-dependent manner
Rui Sheng,
Weikun Meng,
Zhong Zhang,
Qi Yin,
Shuang Jiang,
Qiwen Li,
Xinyan Gan,
Danting Zhang,
Zongke Zhou,
Shuibin Lin,
Mingyue Lyu,
Xingmei Yang,
Quan Yuan
Affiliations
Rui Sheng
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
Weikun Meng
Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
Zhong Zhang
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
Qi Yin
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
Shuang Jiang
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
Qiwen Li
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; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Xinyan Gan
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
Danting Zhang
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
Zongke Zhou
Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
Shuibin Lin
Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
Mingyue Lyu
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; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Xingmei Yang
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; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Quan Yuan
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; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Corresponding author
Summary: Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (m6A), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that m6A 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 m6A-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.
