{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:57:29Z","timestamp":1791457049640,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20200149"],"award-info":[{"award-number":["BK20200149"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Lipoid proteinosis (LP) is a rare autosomal recessive disorder caused by loss\u2010of\u2010function mutations in the extracellular matrix protein 1 (ECM1) gene. While the clinical features of LP are well documented, the cellular mechanisms underlying its oral manifestations, particularly the direct consequences of ECM1 deficiency in oral keratinocytes, remain poorly understood. This study investigated the role of ECM1 in human oral keratinocytes (HOK) using an in\u00a0vitro gain\u2010 and loss\u2010of\u2010function model. Functional assays were performed to evaluate proliferation, migration, keratinization and epithelial\u2010mesenchymal transition (EMT)\u2010like remodelling, complemented by transcriptomic sequencing (RNA\u2010seq) to profile global transcriptional changes. ECM1 knockdown inhibited HOK proliferation and migration, while concomitantly promoting keratinization and an EMT\u2010like remodelling response. Protein\u2010level analyses confirmed activation of the TGF\u2010\u03b2\/Smad signalling pathway, with elevated p\u2010Smad2\/3 and increased secretion of TGF\u2010\u03b21 and MMP\u20109. RNA\u2010seq analysis identified perturbations in genes and pathways governing cell cycle, motility and differentiation. Immunohistochemical validation in LP patient tissue showed COL4A1 deposition matching the characteristic PAS\u2010positive hyaline material. Loss of ECM1 function may contribute to oral LP features through a dual mechanism: impairing tissue repair by hampering keratinocyte proliferation and migration, and promoting tissue remodelling through aberrant keratinization and an EMT\u2010like phenotypic shift. These findings offer a cell\u2010based model for understanding the oral manifestations of LP and highlight the epithelial contribution to LP\u2010associated tissue remodelling.<\/jats:p>","DOI":"10.1111\/exd.70373","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:42:12Z","timestamp":1791456132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ECM1<\/scp>\n                    Loss in Oral Keratinocytes Impairs Proliferation and Migration While Promoting Keratinization and\n                    <scp>EMT<\/scp>\n                    \u2010Like Remodelling: A Cell\u2010Based Model for the Oral Manifestations of Lipoid Proteinosis"],"prefix":"10.1111","volume":"35","author":[{"given":"Suxuan","family":"Xu","sequence":"first","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijing","family":"Xie","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlei","family":"Wu","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5949-3001","authenticated-orcid":false,"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4494-6570","authenticated-orcid":false,"given":"Juan","family":"Wu","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1093\/hmg\/11.7.833","article-title":"Lipoid Proteinosis Maps to 1q21 and Is Caused by Mutations in the Extracellular Matrix Protein 1 Gene (ECM1)","volume":"11","author":"Hamada T.","year":"2002","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.abd.2021.04.010","article-title":"Ultrastructural Aspects of the Skin in Lipoid Proteinosis (Urbach\u2010Wiethe Disease)","volume":"96","author":"Almeida H. L.","year":"2021","journal-title":"Anais Brasileiros de Dermatologia"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1001\/jamadermatol.2018.3435","article-title":"Lipoid Proteinosis","volume":"154","author":"Bhattacharjee R.","year":"2018","journal-title":"JAMA Dermatology"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.4103\/jomfp.jomfp_249_21","article-title":"Lipoid Proteinosis: Review of Indian Cases","volume":"26","author":"Shah J. S.","year":"2022","journal-title":"Journal of Oral and Maxillofacial Pathology"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1007\/s00784-016-2017-7","article-title":"Lipoid Proteinosis Unveiled by Oral Mucosal Lesions: A Comprehensive Analysis of 137 Cases","volume":"21","author":"Frenkel B.","year":"2017","journal-title":"Clinical Oral Investigations"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/ced\/llae039","article-title":"Advances in Treatment for Lipoid Proteinosis (Urbach\u2010Wiethe Disease): A Case Report and Systematic Review","volume":"49","author":"Bueno\u2010Molina R. C.","year":"2024","journal-title":"Clinical and Experimental Dermatology"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1038\/sj.jid.5701231","article-title":"Interaction of Extracellular Matrix Protein 1 With Extracellular Matrix Components: ECM1 Is a Basement Membrane Protein of the Skin","volume":"128","author":"Sercu S.","year":"2008","journal-title":"Journal of Investigative Dermatology"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2174\/1874372201307010029","article-title":"The Extracellular Matrix Protein 1 (ECM1) in Skin Biology: An Update for the Pleiotropic Action","volume":"7","author":"Oyama N.","year":"2013","journal-title":"Open Dermatology Journal"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","DOI":"10.3390\/jfb16100385","article-title":"Opportunities and Risks of Promoting Skin and Bone Healing via Implant Biofunctionalization of Extracellular Matrix Protein ECM1","volume":"16","author":"Braun N. 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L.","year":"2013","journal-title":"Journal of Oral Pathology & Medicine"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1016\/j.oooo.2026.02.010","article-title":"Oral and Maxillofacial Manifestations of Lipoid Proteinosis With a Novel ECM1 Mutation: Case Report and Literature Review","volume":"142","author":"Xu S.","year":"2026","journal-title":"Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology"},{"key":"e_1_2_9_14_1","first-page":"531","article-title":"Lipoid Proteinosis: A Case Report and Literature Review of Chinese Cases","volume":"45","author":"Li Y.","year":"2024","journal-title":"Journal of Capital Medical University"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.lfs.2019.04.029","article-title":"The Maintenance of an Oral Epithelial Barrier","volume":"227","author":"Wang S. 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B.","year":"2002","journal-title":"Journal of Dental Education"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"10660","DOI":"10.3390\/ijms262110660","article-title":"Distinct Molecular Mechanisms in Oral Mucosal Wound Healing: Translational Insights and Future Directions","volume":"26","author":"Chuhuaicura P.","year":"2025","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jdermsci.2020.06.010","article-title":"Gene Silencing of Extracellular Matrix Protein 1 (ECM1) Results in Phenotypic Alterations of Dermal Fibroblasts Reminiscent of Clinical Features of Lichen Sclerosus","volume":"100","author":"Utsunomiya N.","year":"2020","journal-title":"Journal of Dermatological Science"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1096\/fsb2fj990934com","article-title":"Extracellular Matrix Protein 1 (ECM1) Has Angiogenic Properties and Is Expressed by Breast Tumor Cells","volume":"15","author":"Han Z.","year":"2001","journal-title":"FASEB Journal"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41374-020-0415-6","article-title":"ECM1 Secreted by HER2\u2010Overexpressing Breast Cancer Cells Promotes Formation of a Vascular Niche Accelerating Cancer Cell Migration and Invasion","volume":"100","author":"Steinhaeuser S. 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T.","year":"2015","journal-title":"Nature Medicine"},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/nm.3902","article-title":"Epithelial\u2010to\u2010Mesenchymal Transition Induces Cell Cycle Arrest and Parenchymal Damage in Renal Fibrosis","volume":"21","author":"Lovisa S.","year":"2015","journal-title":"Nature Medicine"},{"key":"e_1_2_9_33_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2021.737570","article-title":"Epithelial\u2010to\u2010Mesenchymal Transition in Fibrosis: Concepts and Targeting Strategies","volume":"12","author":"Lovisa S.","year":"2021","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_9_34_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.0906-6705.2006.00409.x","article-title":"Extracellular Matrix Protein 1 Inhibits the Activity of Matrix Metalloproteinase 9 Through High\u2010Affinity Protein\/Protein Interactions","volume":"15","author":"Fujimoto N.","year":"2006","journal-title":"Experimental Dermatology"},{"key":"e_1_2_9_35_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1101\/gad.14.2.163","article-title":"Cell Surface\u2010Localized Matrix Metalloproteinase\u20109 Proteolytically Activates TGF\u2010\u03b2 and Promotes Tumor Invasion and Angiogenesis","volume":"14","author":"Yu Q.","year":"2000","journal-title":"Genes & Development"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","first-page":"L1006","DOI":"10.1152\/ajplung.00015.2014","article-title":"Matrix Metalloproteinase\u20109 Activates TGF\u2010\u03b2 and Stimulates Fibroblast Contraction of Collagen Gels","volume":"306","author":"Kobayashi T.","year":"2014","journal-title":"American Journal of Physiology. Lung Cellular and Molecular Physiology"},{"key":"e_1_2_9_37_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1046\/j.1523-1747.2002.01641.x","article-title":"Transforming Growth Factor\u2010Beta Signaling Through the Smad Pathway: Role in Extracellular Matrix Gene Expression and Regulation","volume":"118","author":"Verrecchia F.","year":"2002","journal-title":"Journal of Investigative Dermatology"},{"key":"e_1_2_9_38_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/jcp.21869","article-title":"Cytokines and Signaling Pathways Regulating Matrix Metalloproteinase\u20109 (MMP\u20109) Expression in Corneal Epithelial Cells","volume":"221","author":"Gordon G. M.","year":"2009","journal-title":"Journal of Cellular Physiology"},{"key":"e_1_2_9_39_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1430187","article-title":"TGF\u2010\u03b2 and TNF\u2010\u03b1 Interaction Promotes the Expression of MMP\u20109 Through H3K36 Dimethylation: Implications in Breast Cancer Metastasis","volume":"15","author":"Kochumon S.","year":"2024","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_9_40_1","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1053\/j.gastro.2019.07.036","article-title":"ECM1 Prevents Activation of Transforming Growth Factor \u03b2, Hepatic Stellate Cells, and Fibrogenesis in Mice","volume":"157","author":"Fan W.","year":"2019","journal-title":"Gastroenterology"},{"key":"e_1_2_9_41_1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1136\/gutjnl-2024-333213","article-title":"ECM1 Attenuates Hepatic Fibrosis by Interfering With Mediators of Latent TGF\u2010\u03b21 Activation","volume":"74","author":"Link F.","year":"2025","journal-title":"Gut"}],"container-title":["Experimental Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/exd.70373","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/exd.70373","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/exd.70373","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:42:20Z","timestamp":1791456140000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/exd.70373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/exd.70373"],"URL":"https:\/\/doi.org\/10.1111\/exd.70373","archive":["Portico"],"relation":{},"ISSN":["0906-6705","1600-0625"],"issn-type":[{"value":"0906-6705","type":"print"},{"value":"1600-0625","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-03-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70373"}}