ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression
Abstract Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-01059-0 |
| _version_ | 1797699537397088256 |
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| author | Guiwen Ye Jinteng Li Wenhui Yu Zhongyu Xie Guan Zheng Wenjie Liu Shan Wang Qian Cao Jiajie Lin Zepeng Su Dateng Li Yunshu Che Shuai Fan Peng Wang Yanfeng Wu Huiyong Shen |
| author_facet | Guiwen Ye Jinteng Li Wenhui Yu Zhongyu Xie Guan Zheng Wenjie Liu Shan Wang Qian Cao Jiajie Lin Zepeng Su Dateng Li Yunshu Che Shuai Fan Peng Wang Yanfeng Wu Huiyong Shen |
| author_sort | Guiwen Ye |
| collection | DOAJ |
| description | Abstract Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that plays an important role in regulating cell biological functions, and ALKBH5 is one of the key m6A demethylases. However, the role of m6A and ALKBH5 in MSC senescence is still unclear. Here, we found that the m6A level was enhanced and ALKBH5 expression was decreased in aging MSCs induced by multiple replications, H2O2 stimulation or UV irradiation. Downregulation of ALKBH5 expression facilitated MSC senescence by enhancing the stability of CYP1B1 mRNA and inducing mitochondrial dysfunction. In addition, IGF2BP1 was identified as the m6A reader restraining the degradation of m6A-modified CYP1B1 mRNA. Furthermore, Alkbh5 knockout in MSCs aggravated spontaneous OA in mice, and overexpression of Alkbh5 improved the efficacy of MSCs in OA. Overall, this study revealed a novel mechanism of m6A in MSC senescence and identified promising targets to protect against aging and OA. |
| first_indexed | 2024-03-12T04:10:15Z |
| format | Article |
| id | doaj.art-c3d74780c03447edbf9a4330bbe79167 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-12T04:10:15Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-c3d74780c03447edbf9a4330bbe791672023-09-03T11:07:05ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-08-015581743175610.1038/s12276-023-01059-0ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progressionGuiwen Ye0Jinteng Li1Wenhui Yu2Zhongyu Xie3Guan Zheng4Wenjie Liu5Shan Wang6Qian Cao7Jiajie Lin8Zepeng Su9Dateng Li10Yunshu Che11Shuai Fan12Peng Wang13Yanfeng Wu14Huiyong Shen15Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityCenter for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen UniversityCenter for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Statistical Science, Southern Methodist UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityCenter for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen UniversityAbstract Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that plays an important role in regulating cell biological functions, and ALKBH5 is one of the key m6A demethylases. However, the role of m6A and ALKBH5 in MSC senescence is still unclear. Here, we found that the m6A level was enhanced and ALKBH5 expression was decreased in aging MSCs induced by multiple replications, H2O2 stimulation or UV irradiation. Downregulation of ALKBH5 expression facilitated MSC senescence by enhancing the stability of CYP1B1 mRNA and inducing mitochondrial dysfunction. In addition, IGF2BP1 was identified as the m6A reader restraining the degradation of m6A-modified CYP1B1 mRNA. Furthermore, Alkbh5 knockout in MSCs aggravated spontaneous OA in mice, and overexpression of Alkbh5 improved the efficacy of MSCs in OA. Overall, this study revealed a novel mechanism of m6A in MSC senescence and identified promising targets to protect against aging and OA.https://doi.org/10.1038/s12276-023-01059-0 |
| spellingShingle | Guiwen Ye Jinteng Li Wenhui Yu Zhongyu Xie Guan Zheng Wenjie Liu Shan Wang Qian Cao Jiajie Lin Zepeng Su Dateng Li Yunshu Che Shuai Fan Peng Wang Yanfeng Wu Huiyong Shen ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression Experimental and Molecular Medicine |
| title | ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression |
| title_full | ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression |
| title_fullStr | ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression |
| title_full_unstemmed | ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression |
| title_short | ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression |
| title_sort | alkbh5 facilitates cyp1b1 mrna degradation via m6a demethylation to alleviate msc senescence and osteoarthritis progression |
| url | https://doi.org/10.1038/s12276-023-01059-0 |
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