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In this study, we reveal the molecular mechanisms of WTAP\/YTHDF2\u2010mediated m6A modification in abnormal stress\u2010induced intervertebral disc (IVD) matrix degradation. WTAP expression in human nucleus pulposus cells was elevated under tension. Similarly, high WTAP expression was detected in severe degenerated human and rat nucleus pulposus tissues. Functionally, WTAP was found to increase the TIMP3 transcript methylation level under tension, resulting in YTHDF2 recognition, binding, and induction of its degradation. Reduction in TIMP3 caused increases in active matrix metalloproteinases, ultimately inducing extracellular matrix degradation in nucleus pulposus cells. Macroscopically, this promotes IDD. Additionally, in vitro and in vivo inhibition of WTAP expression or TIMP3 overexpression significantly increased stress resistance in the nucleus pulposus, thereby alleviating IDD. Our results show that abnormal stress disrupts IVD\u00a0matrix stability through WTAP\/YTHDF2\u2010dependent TIMP3 m6A modification.<\/jats:p>","DOI":"10.1002\/jcp.31219","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T14:14:59Z","timestamp":1707747299000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Abnormal stress promotes intervertebral disc degeneration through WTAP\/YTHDF2\u2010dependent TIMP3 m6A modification"],"prefix":"10.1002","volume":"239","author":[{"given":"Daokuan","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Spine Surgery Yijishan Hospital of Wannan Medical College Wuhu Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quanlai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Yijishan Hospital of Wannan Medical College Wuhu Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Non\u2010Coding RNA Transformation Research of Anhui Higher Education Institution Wuhu Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Spine Research Center of Wannan Medical College Wuhu Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5779-6092","authenticated-orcid":false,"given":"Liang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Spine Research Center of Wannan Medical College Wuhu Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A4498"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249739"},{"key":"e_1_2_9_4_1","first-page":"1","article-title":"Oxidative stress aggravates apoptosis of nucleus pulposus cells through m(6)A modification of MAT2A pre\u2010mRNA by METTL16","volume":"2022","author":"Chen P. 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