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This study investigated whether differential epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant responses, is associated with distinct antioxidant capacities between these cartilage types. Cartilage tissues from 5-week-old male ICR mice (n = 16 for gene analyses, n = 8 for protein analyses) were obtained using laser microdissection. Gene and protein expression was analyzed by microarray, real-time RT-PCR, and immunohistochemistry. DNA methylation of the Nrf2 promoter was evaluated using pyrosequencing and high-resolution melting analysis. Nrf2 expression in MCC was approximately 1\/10 that in TAC at mRNA level and only 5% at protein level. Downstream antioxidant enzymes (NQO1, G6PD, HO-1) showed significantly reduced expression in MCC. Oxidative DNA damage marker 8-OHdG was significantly elevated in MCC compared to TAC (20.0% vs. 10.7%, p &lt; 0.05). The Nrf2 promoter region showed higher DNA methylation levels in MCC, confirmed by high-resolution melting analysis. Higher Nrf2 promoter methylation in MCC is associated with reduced antioxidant capacity and elevated oxidative damage. This epigenetic\u2013antioxidant relationship may contribute to MCC\u2019s vulnerability to mechanical stress-induced degeneration and represents a potential therapeutic target for temporomandibular joint disorders.<\/jats:p>","DOI":"10.3390\/antiox15070854","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:56:42Z","timestamp":1783349802000},"page":"854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Promoter Hypermethylation Is Associated with Reduced Nrf2 and Antioxidant Enzyme Expression in Mandibular Condylar Cartilage in Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Hisano","family":"Ujiie","sequence":"first","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3473-1218","authenticated-orcid":false,"given":"Hiroyuki","family":"Kanzaki","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"},{"name":"Department of Orthodontics, Tohoku University Hospital, 4-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Katayama","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Ida","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syunnosuke","family":"Tohyama","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Shimoyama","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1927-9201","authenticated-orcid":false,"given":"Misao","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tomonari","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1177\/1941738109350438","article-title":"The basic science of articular cartilage: Structure, composition, and function","volume":"1","author":"Bedi","year":"2009","journal-title":"Sports Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1242\/dev.127.8.1671","article-title":"Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis","volume":"127","author":"Chai","year":"2000","journal-title":"Development"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0003-9969(96)00021-0","article-title":"An immunohistochemical study of regional differences in the distribution of type i and type ii collagens in rat mandibular condylar cartilage","volume":"41","author":"Mizoguchi","year":"1996","journal-title":"Arch. 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