1. METTL3 regulates cartilage development and homeostasis by affecting Lats1 mRNA stability in an m 6 A-YTHDF2-dependent manner.
- Author
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Sheng R, Meng W, Zhang Z, Yin Q, Jiang S, Li Q, Gan X, Zhang D, Zhou Z, Lin S, Lyu M, Yang X, and Yuan Q
- Subjects
- Animals, Mice, YAP-Signaling Proteins metabolism, Mice, Knockout, Osteoarthritis metabolism, Osteoarthritis genetics, Osteoarthritis pathology, RNA, Messenger metabolism, RNA, Messenger genetics, Cartilage, Articular metabolism, Cartilage, Articular pathology, Cartilage metabolism, Mice, Inbred C57BL, Chondrogenesis genetics, Methylation, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Humans, Male, Mandibular Condyle metabolism, Methyltransferases metabolism, Methyltransferases genetics, Homeostasis, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Chondrocytes metabolism, RNA Stability, Adenosine analogs & derivatives, Adenosine metabolism, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics
- Abstract
Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (m
6 A), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that m6 A 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 m6 A-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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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