{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:12:16Z","timestamp":1778760736921,"version":"3.51.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005639","name":"Universidade De S\u00e3o Paulo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005639","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biol Rep"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>This study investigated the biological mechanisms underlying temporomandibular disorder (TMD) pain in monozygotic twins discordant for the condition, isolating environmental factors from genetic influence. Twenty women (ten pairs of discordant twins) underwent standardized examinations and venous plasma analysis. Inflammatory biomarkers (IL-6, IL-10), oxidative markers (MDA, SOD, catalase), matrix remodeling proteins (MMP-2, MMP-9, TIMP-1, TIMP-2), and neurotrophic factors (BDNF, \u03b2-NGF, \u03b12M) were measured. Twins with painful TMD demonstrated greater pain severity, functional interference, and mechanical sensitivity compared to discordant controls. Significant within-pair differences were identified in IL-6, IL-6\/IL-10 ratio, MDA\/SOD ratio, MMP-9, TIMP-2, and BDNF levels. Pro-inflammatory and oxidative indices positively correlated with pain intensity and palpation sensitivity, while reduced BDNF associated with greater symptom burden. Principal component analysis revealed a dominant inflammatory-oxidative profile that discriminated painful twins from controls. In genetically identical individuals, painful TMD associates with selective peripheral biological alterations involving inflammation, oxidative imbalance, and extracellular matrix remodeling. These findings could demonstrate that environmental and experiential factors biologically may contribute to vulnerability to chronic orofacial pain, highlighting the importance of epigenetic mechanisms in TMD pathogenesis beyond genetic predisposition. This article identifies specific peripheral biomarker profiles distinguishing monozygotic twins with and without painful TMD, and could show that inflammation, oxidative imbalance, matrix remodeling, and reduced neurotrophic support characterize the painful phenotype. These mechanistic insights could enable clinicians to develop targeted, biologically informed therapeutic strategies and potentially predict pain vulnerability in genetically susceptible individuals.<\/jats:p>","DOI":"10.1007\/s11033-026-11902-y","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:49:50Z","timestamp":1778759390000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory, oxidative, and neurotrophic profiles in monozygotic twins discordant for pain-related TMD"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8050-4396","authenticated-orcid":false,"given":"La\u00eds Valencise","family":"Magri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-1242","authenticated-orcid":false,"given":"Melissa Oliveira","family":"Melchior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2942-7066","authenticated-orcid":false,"given":"Cec\u00edlia Nogueira Tavares","family":"Peixeiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-2642","authenticated-orcid":false,"given":"Vit\u00f3ria Carolina","family":"Rondon-Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-4045","authenticated-orcid":false,"given":"Margarete","family":"Ribeiro-Dasilva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9497-0005","authenticated-orcid":false,"given":"Kranya Victoria","family":"D\u00edaz-Serrano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3738-2036","authenticated-orcid":false,"given":"Riccardo","family":"Lacchini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-6650","authenticated-orcid":false,"given":"Edilaine Cristina","family":"da Silva Gherardi-Donato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-2730","authenticated-orcid":false,"given":"Christie Ramos Andrade","family":"Leite-Panissi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"issue":"10","key":"11902_CR1","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1177\/0022034516653743","volume":"95","author":"GD Slade","year":"2016","unstructured":"Slade GD, Ohrbach R, Greenspan JD, Fillingim RB, Bair E, Sanders AE et al (2016) Painful temporomandibular disorder: decade of discovery from OPPERA studies. J Dent Res 95(10):1084\u20131092. https:\/\/doi.org\/10.1177\/0022034516653743","journal-title":"J Dent Res"},{"issue":"12 Suppl","key":"11902_CR2","doi-asserted-by":"publisher","first-page":"T75","DOI":"10.1016\/j.jpain.2013.06.009","volume":"14","author":"RB Fillingim","year":"2013","unstructured":"Fillingim RB, Ohrbach R, Greenspan JD, Knott C, Diatchenko L, Dubner R et al (2013) Psychological factors associated with development of TMD: the OPPERA prospective cohort study. J Pain 14(12 Suppl):T75\u201390. https:\/\/doi.org\/10.1016\/j.jpain.2013.06.009","journal-title":"J Pain"},{"issue":"1","key":"11902_CR3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s10194-020-01131-4","volume":"21","author":"Y Yin","year":"2020","unstructured":"Yin Y, He S, Xu J, You W, Li Q, Long J et al (2020) The neuro-pathophysiology of temporomandibular disorders-related pain: a systematic review of structural and functional MRI studies. J Headache Pain 21(1):78. https:\/\/doi.org\/10.1186\/s10194-020-01131-4","journal-title":"J Headache Pain"},{"issue":"5","key":"11902_CR4","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1111\/joor.12263","volume":"42","author":"CM Visscher","year":"2015","unstructured":"Visscher CM, Lobbezoo F (2015) TMD pain is partly heritable. A systematic review of family studies and genetic association studies. J Oral Rehabil 42(5):386\u2013399. https:\/\/doi.org\/10.1111\/joor.12263","journal-title":"J Oral Rehabil"},{"issue":"4","key":"11902_CR5","doi-asserted-by":"publisher","first-page":"e0320515","DOI":"10.1371\/journal.pone.0320515","volume":"20","author":"LV Magri","year":"2025","unstructured":"Magri LV, Melchior MO, da Silva GV, Gherardi-Donato ECDS, Leite-Panissi CRA (2025) Phenotypes of painful TMD in discordant monozygotic twins according to a cognitive-behavioral-emotional model: a case-control study. PLoS ONE 20(4):e0320515. https:\/\/doi.org\/10.1371\/journal.pone.0320515","journal-title":"PLoS ONE"},{"issue":"6","key":"11902_CR6","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1007\/s00784-024-05699-y","volume":"28","author":"RS Salbego","year":"2024","unstructured":"Salbego RS, Conti PCR, Soares FFC, Ferreira DMAO, Herreira-Ferreira M, de Lima-Netto BA et al (2024) Influence of psychometric and sleep quality features on painful mechanical sensitivity and pain modulation in patients with temporomandibular disorders. Clin Oral Investig 28(6):302. https:\/\/doi.org\/10.1007\/s00784-024-05699-y","journal-title":"Clin Oral Investig"},{"issue":"2","key":"11902_CR7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.11607\/ofph.2016","volume":"32","author":"CM Visscher","year":"2018","unstructured":"Visscher CM, Schouten MJ, Ligthart L, van Houtem CM, de Jongh A, Boomsma DI (2018) Shared genetics of temporomandibular disorder pain and neck pain: results of a twin study. J Oral Facial Pain Headache 32(2):107\u2013112. https:\/\/doi.org\/10.11607\/ofph.2016","journal-title":"J Oral Facial Pain Headache"},{"issue":"2","key":"11902_CR8","first-page":"91","volume":"26","author":"O Plesh","year":"2012","unstructured":"Plesh O, Noonan C, Buchwald DS, Goldberg J, Afari N (2012) Temporomandibular disorder-type pain and migraine headache in women: a preliminary twin study. J Orofac Pain 26(2):91\u201398","journal-title":"J Orofac Pain"},{"issue":"1","key":"11902_CR9","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1179\/crn.2007.005","volume":"25","author":"Y Matsuka","year":"2007","unstructured":"Matsuka Y, Nagamatsu C, Itoh S, Tomonari T, Makki A, Minakuchi H et al (2007) Comparison of inter-twin concordance in symptoms of temporomandibular disorders: a preliminary investigation in an adolescent twin population. Cranio 25(1):23\u201329. https:\/\/doi.org\/10.1179\/crn.2007.005","journal-title":"Cranio"},{"issue":"4","key":"11902_CR10","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.tins.2015.02.001","volume":"38","author":"G Descalzi","year":"2015","unstructured":"Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M (2015) Epigenetic mechanisms of chronic pain. Trends Neurosci 38(4):237\u2013246. https:\/\/doi.org\/10.1016\/j.tins.2015.02.001","journal-title":"Trends Neurosci"},{"key":"11902_CR11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1756-8935-3-11","volume":"3","author":"A Hellman","year":"2010","unstructured":"Hellman A, Chess A (2010) Extensive sequence-influenced DNA methylation polymorphism in the human genome. Epigenetics Chromatin 3:11. https:\/\/doi.org\/10.1186\/1756-8935-3-11","journal-title":"Epigenetics Chromatin"},{"issue":"5","key":"11902_CR12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3390\/diagnostics10050303","volume":"10","author":"A Zwiri","year":"2020","unstructured":"Zwiri A, Al-Hatamleh MAI, Ahmad WMAW, Asif JA, Khoo SP, Husein A et al (2020) Biomarkers for temporomandibular disorders: current status and future directions. Diagnostics 10(5):303. 10. 390\/diagnostics10050303","journal-title":"Diagnostics"},{"issue":"3","key":"11902_CR13","doi-asserted-by":"publisher","first-page":"354","DOI":"10.4103\/njms.njms_136_22","volume":"14","author":"A Shekhar","year":"2023","unstructured":"Shekhar A, Maddheshiya N, Nair V, Rastogi V, Srivastava A, Singh AK (2023) Salivary biomarkers and temporomandibular disorders: A systematic review. Natl J Maxillofac Surg 14(3):354\u2013359. https:\/\/doi.org\/10.4103\/njms.njms_136_22","journal-title":"Natl J Maxillofac Surg"},{"issue":"2","key":"11902_CR14","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1111\/joor.13589","volume":"51","author":"MK Alam","year":"2024","unstructured":"Alam MK, Zaman MU, Alqhtani NR, Alqahtani AS, Alqahtani F, Cicci\u00f9 M, Minervini G (2024) Salivary biomarkers and temporomandibular disorders: a systematic review. J Oral Rehabil 51(2):416\u2013426. https:\/\/doi.org\/10.1111\/joor.13589","journal-title":"J Oral Rehabil"},{"issue":"4","key":"11902_CR15","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1080\/08869634.2023.2229607","volume":"43","author":"Y Aoun","year":"2025","unstructured":"Aoun Y, Ejbeh R, Youssef A, Hobeiche J (2025) Salivary biomarkers as potential diagnostic tool for temporomandibular disorders: A comprehensive review. Cranio 43(4):603\u2013612. https:\/\/doi.org\/10.1080\/08869634.2023.2229607","journal-title":"Cranio"},{"issue":"8","key":"11902_CR16","doi-asserted-by":"publisher","first-page":"3668","DOI":"10.3390\/ijms26083668","volume":"26","author":"S Wen","year":"2025","unstructured":"Wen S, Santander J, Barria D, Salazar LA, Sandoval C, Arias C, Iturriaga V (2025) Epigenetic Biomarkers in temporomandibular joint osteoarthritis: an emerging target in treatment. Int J Mol Sci 26(8):3668. https:\/\/doi.org\/10.3390\/ijms26083668","journal-title":"Int J Mol Sci"},{"key":"11902_CR17","doi-asserted-by":"publisher","unstructured":"Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet J-P et al (2014) Diagnostic criteria for temporomandibular disorders (dc\/tmd) for clinical and research applications: recommendations of the international RDC\/TMD consortium network * and orofacial pain special interest group \u2020 HHS Public Access. J Oral Facial Pain Headache.28(1): 6-27. https:\/\/doi.org\/10.11607\/jop.1151","DOI":"10.11607\/jop.1151"},{"issue":"2","key":"11902_CR18","doi-asserted-by":"publisher","first-page":"R245","DOI":"10.1152\/ajpregu.00920.2005","volume":"291","author":"JJ Sherman","year":"2006","unstructured":"Sherman JJ, LeResche L (2006) Does experimental pain response vary across the menstrual cycle? A methodological review. Am J Physiol Regul Integr Comp Physiol 291(2):R245\u2013R256. https:\/\/doi.org\/10.1152\/ajpregu.00920.2005","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"5","key":"11902_CR19","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1210\/er.2007-0001","volume":"28","author":"RH Straub","year":"2007","unstructured":"Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28(5):521\u2013574. https:\/\/doi.org\/10.1210\/er.2007-0001","journal-title":"Endocr Rev"},{"issue":"4","key":"11902_CR20","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s00520-010-0844-7","volume":"19","author":"KA Ferreira","year":"2011","unstructured":"Ferreira KA, Teixeira MJ, Mendonza TR, Cleeland CS (2011) Validation of brief pain inventory to Brazilian patients with pain. Supportive care cancer: official J Multinational Association Supportive Care Cancer 19(4):505\u2013511. https:\/\/doi.org\/10.1007\/s00520-010-0844-7","journal-title":"Supportive care cancer: official J Multinational Association Supportive Care Cancer"},{"issue":"12","key":"11902_CR21","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/s41577-020-00463-2","volume":"21","author":"PM Grace","year":"2021","unstructured":"Grace PM, Hutchinson MR, Maier SF, Watkins LR (2021) The neuroimmunology of chronic pain. Nat Rev Immunol 21(12):667\u2013685. https:\/\/doi.org\/10.1038\/s41577-020-00463-2","journal-title":"Nat Rev Immunol"},{"issue":"10","key":"11902_CR22","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/nrn3784","volume":"15","author":"RR Ji","year":"2014","unstructured":"Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Neurosci 15(10):533\u2013550. https:\/\/doi.org\/10.1038\/nrn3784","journal-title":"Nat Rev Neurosci"},{"issue":"8","key":"11902_CR23","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1097\/j.pain.0000000000002811","volume":"164","author":"M Cobourne-Dyer","year":"2023","unstructured":"Cobourne-Dyer M, Li Y, Gabriel S et al (2023) Oxidative stress mechanisms in chronic pain: clinical implications. Pain 164(8):1558\u20131573. https:\/\/doi.org\/10.1097\/j.pain.0000000000002811","journal-title":"Pain"},{"issue":"3","key":"11902_CR24","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41591-021-01335-z","volume":"27","author":"I Tracey","year":"2021","unstructured":"Tracey I, Woolf CJ (2021) Personalized pain medicine: future directions. Nat Med 27(3):412\u2013427. https:\/\/doi.org\/10.1038\/s41591-021-01335-z","journal-title":"Nat Med"},{"issue":"6","key":"11902_CR25","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.tins.2020.12.006","volume":"44","author":"AM Hagenston","year":"2021","unstructured":"Hagenston AM, Bading H (2021) Calcium signaling in chronic pain-related plasticity. Trends Neurosci 44(6):467\u2013481. https:\/\/doi.org\/10.1016\/j.tins.2020.12.006","journal-title":"Trends Neurosci"},{"issue":"4","key":"11902_CR26","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/s41582-022-00626-2","volume":"18","author":"F Denk","year":"2022","unstructured":"Denk F, McMahon SB (2022) Neuroepigenetics in chronic pain. Nat Rev Neurol 18(4):247\u2013258. https:\/\/doi.org\/10.1038\/s41582-022-00626-2","journal-title":"Nat Rev Neurol"},{"key":"11902_CR27","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1146\/annurev-neuro-082121-120942","volume":"45","author":"K Bannister","year":"2022","unstructured":"Bannister K, Dickenson AH (2022) NGF and the rising role of neuroimmune interactions in pain. Annu Rev Neurosci 45:493\u2013516. https:\/\/doi.org\/10.1146\/annurev-neuro-082121-120942","journal-title":"Annu Rev Neurosci"},{"issue":"7","key":"11902_CR28","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1097\/j.pain.0000000000002836","volume":"164","author":"M Snyder","year":"2023","unstructured":"Snyder M et al (2023) Epigenetic mechanisms and chronic musculoskeletal pain. Pain 164(7):1239\u20131249. https:\/\/doi.org\/10.1097\/j.pain.0000000000002836","journal-title":"Pain"},{"issue":"5","key":"11902_CR29","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrrheum.2018.32","volume":"14","author":"FMK Williams","year":"2018","unstructured":"Williams FMK, Spector TD (2018) Pain: genetic factors and twin studies. Nat Rev Rheumatol 14(5):327\u2013338. https:\/\/doi.org\/10.1038\/nrrheum.2018.32","journal-title":"Nat Rev Rheumatol"},{"issue":"8","key":"11902_CR30","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1111\/joor.13487","volume":"50","author":"MJ Teixeira","year":"2023","unstructured":"Teixeira MJ, Ayesh EE et al (2023) Biomarkers in temporomandibular disorders: mechanisms and clinical translation. J Oral Rehabil 50(8):916\u2013938. https:\/\/doi.org\/10.1111\/joor.13487","journal-title":"J Oral Rehabil"}],"container-title":["Molecular Biology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11033-026-11902-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11033-026-11902-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11033-026-11902-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:49:51Z","timestamp":1778759391000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11033-026-11902-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,12]]}},"alternative-id":["11902"],"URL":"https:\/\/doi.org\/10.1007\/s11033-026-11902-y","relation":{},"ISSN":["0301-4851","1573-4978"],"issn-type":[{"value":"0301-4851","type":"print"},{"value":"1573-4978","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"assertion":[{"value":"6 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"During the preparation of this work the author(s) used ChatGPT (OpenAI) to improve the clarity, grammar, and readability of the manuscript. After using this tool\/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of generative AI and AI-assisted technologies in the manuscript preparation process"}}],"article-number":"764"}}