FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis
Abstract 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,...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-10-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01330-y |
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| _version_ | 1846172236153618432 |
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| author | Hongyi Zhou Ziang Xie Yu Qian Weiyu Ni Lei Cui Xiangqian Fang Shuanglin Wan Xiangde Zhao An Qin Shunwu Fan Yizheng Wu |
| author_facet | Hongyi Zhou Ziang Xie Yu Qian Weiyu Ni Lei Cui Xiangqian Fang Shuanglin Wan Xiangde Zhao An Qin Shunwu Fan Yizheng Wu |
| author_sort | Hongyi Zhou |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-4c577424afc64586869ae5acc3995191 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-4c577424afc64586869ae5acc39951912024-11-10T12:09:48ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132024-10-0156102283229510.1038/s12276-024-01330-yFTO-mediated SMAD2 m6A modification protects cartilage against OsteoarthritisHongyi Zhou0Ziang Xie1Yu Qian2Weiyu Ni3Lei Cui4Xiangqian Fang5Shuanglin Wan6Xiangde Zhao7An Qin8Shunwu Fan9Yizheng Wu10Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineCollaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical UniversityDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract 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.https://doi.org/10.1038/s12276-024-01330-y |
| spellingShingle | Hongyi Zhou Ziang Xie Yu Qian Weiyu Ni Lei Cui Xiangqian Fang Shuanglin Wan Xiangde Zhao An Qin Shunwu Fan Yizheng Wu FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis Experimental and Molecular Medicine |
| title | FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis |
| title_full | FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis |
| title_fullStr | FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis |
| title_full_unstemmed | FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis |
| title_short | FTO-mediated SMAD2 m6A modification protects cartilage against Osteoarthritis |
| title_sort | fto mediated smad2 m6a modification protects cartilage against osteoarthritis |
| url | https://doi.org/10.1038/s12276-024-01330-y |
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