{"title":"METTL14 通过 GPX4 的 m6A 修饰促进骨关节炎中软骨细胞的铁变态反应。","authors":"Dawei Liu, Liang Ren, Jun Liu","doi":"10.1111/1756-185X.15297","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Ferroptosis is caused by iron-dependent peroxidation of membrane phospholipids and chondrocyte ferroptosis contributes to osteoarthritis (OA) progression. Glutathione peroxidase 4 (GPX4) plays a master role in blocking ferroptosis. N6-methyladenosine (m6A) is an epigenetic modification among mRNA post-transcriptional modifications. This study investigated the effect of methyltransferase-like 14 (METTL14), the key component of the m6A methyltransferase, on chondrocyte ferroptosis via m6A modification.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>An OA rat model was established through an intra-articular injection of monosodium iodoacetate in the right knee. OA cartilages in rat models were used for gene expression analysis. Primary mouse chondrocytes or ADTC5 cells were stimulated with IL-1β or erastin. The m6A RNA methylation quantification kit was used to measure m6A level. The effect of METTL14 and GPX4 on ECM degradation and ferroptosis was investigated through western blotting, fluorescence immunostaining, propidium iodide staining, and commercially available kits. The mechanism of METTL14 action was explored through MeRIP-qPCR assays.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>METTL14 and m6A expression was upregulated in osteoarthritic cartilages and IL-1β-induced chondrocytes. METTL14 depletion repressed the IL-1β or erastin-stimulated ECM degradation and ferroptosis in mouse chondrocytes. METTL14 inhibited GPX4 gene through m6A methylation modification. GPX4 knockdown reversed the si-METTL14-mediated protection in IL-1β-induced chondrocytes.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>METTL14 depletion inhibits ferroptosis and ECM degradation by suppressing GPX4 mRNA m6A modification in injured chondrocytes.</p>\n </section>\n </div>","PeriodicalId":14330,"journal":{"name":"International Journal of Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"METTL14 promotes chondrocyte ferroptosis in osteoarthritis via m6A modification of GPX4\",\"authors\":\"Dawei Liu, Liang Ren, Jun Liu\",\"doi\":\"10.1111/1756-185X.15297\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Ferroptosis is caused by iron-dependent peroxidation of membrane phospholipids and chondrocyte ferroptosis contributes to osteoarthritis (OA) progression. Glutathione peroxidase 4 (GPX4) plays a master role in blocking ferroptosis. N6-methyladenosine (m6A) is an epigenetic modification among mRNA post-transcriptional modifications. This study investigated the effect of methyltransferase-like 14 (METTL14), the key component of the m6A methyltransferase, on chondrocyte ferroptosis via m6A modification.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>An OA rat model was established through an intra-articular injection of monosodium iodoacetate in the right knee. OA cartilages in rat models were used for gene expression analysis. Primary mouse chondrocytes or ADTC5 cells were stimulated with IL-1β or erastin. The m6A RNA methylation quantification kit was used to measure m6A level. The effect of METTL14 and GPX4 on ECM degradation and ferroptosis was investigated through western blotting, fluorescence immunostaining, propidium iodide staining, and commercially available kits. The mechanism of METTL14 action was explored through MeRIP-qPCR assays.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>METTL14 and m6A expression was upregulated in osteoarthritic cartilages and IL-1β-induced chondrocytes. METTL14 depletion repressed the IL-1β or erastin-stimulated ECM degradation and ferroptosis in mouse chondrocytes. METTL14 inhibited GPX4 gene through m6A methylation modification. GPX4 knockdown reversed the si-METTL14-mediated protection in IL-1β-induced chondrocytes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>METTL14 depletion inhibits ferroptosis and ECM degradation by suppressing GPX4 mRNA m6A modification in injured chondrocytes.</p>\\n </section>\\n </div>\",\"PeriodicalId\":14330,\"journal\":{\"name\":\"International Journal of Rheumatic Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2024-08-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Rheumatic Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.15297\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.15297","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
METTL14 promotes chondrocyte ferroptosis in osteoarthritis via m6A modification of GPX4
Background
Ferroptosis is caused by iron-dependent peroxidation of membrane phospholipids and chondrocyte ferroptosis contributes to osteoarthritis (OA) progression. Glutathione peroxidase 4 (GPX4) plays a master role in blocking ferroptosis. N6-methyladenosine (m6A) is an epigenetic modification among mRNA post-transcriptional modifications. This study investigated the effect of methyltransferase-like 14 (METTL14), the key component of the m6A methyltransferase, on chondrocyte ferroptosis via m6A modification.
Methods
An OA rat model was established through an intra-articular injection of monosodium iodoacetate in the right knee. OA cartilages in rat models were used for gene expression analysis. Primary mouse chondrocytes or ADTC5 cells were stimulated with IL-1β or erastin. The m6A RNA methylation quantification kit was used to measure m6A level. The effect of METTL14 and GPX4 on ECM degradation and ferroptosis was investigated through western blotting, fluorescence immunostaining, propidium iodide staining, and commercially available kits. The mechanism of METTL14 action was explored through MeRIP-qPCR assays.
Results
METTL14 and m6A expression was upregulated in osteoarthritic cartilages and IL-1β-induced chondrocytes. METTL14 depletion repressed the IL-1β or erastin-stimulated ECM degradation and ferroptosis in mouse chondrocytes. METTL14 inhibited GPX4 gene through m6A methylation modification. GPX4 knockdown reversed the si-METTL14-mediated protection in IL-1β-induced chondrocytes.
Conclusion
METTL14 depletion inhibits ferroptosis and ECM degradation by suppressing GPX4 mRNA m6A modification in injured chondrocytes.
期刊介绍:
The International Journal of Rheumatic Diseases (formerly APLAR Journal of Rheumatology) is the official journal of the Asia Pacific League of Associations for Rheumatology. The Journal accepts original articles on clinical or experimental research pertinent to the rheumatic diseases, work on connective tissue diseases and other immune and allergic disorders. The acceptance criteria for all papers are the quality and originality of the research and its significance to our readership. Except where otherwise stated, manuscripts are peer reviewed by two anonymous reviewers and the Editor.