{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:20Z","timestamp":1787028440198,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008604","name":"Scleroderma and Raynaud's UK","doi-asserted-by":"publisher","award":["RRF-UCL-2"],"award-info":[{"award-number":["RRF-UCL-2"]}],"id":[{"id":"10.13039\/501100008604","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017158","name":"Royal Free Hospital","doi-asserted-by":"publisher","award":["RRF-UCL-2"],"award-info":[{"award-number":["RRF-UCL-2"]}],"id":[{"id":"10.13039\/100017158","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Excessive cross-linking is a major factor in the resistance to the remodelling of the extracellular matrix (ECM) during fibrotic progression. The role of TGF\u03b2 signalling in impairing ECM remodelling has been demonstrated in various fibrotic models. We hypothesised that increased ECM cross-linking by TGF\u03b2 contributes to skin fibrosis in Systemic Sclerosis (SSc). Proteomics was used to identify cross-linking enzymes in the ECM of primary human dermal fibroblasts, and to compare their levels following treatment with TGF\u03b2-1. A significant upregulation and enrichment of lysyl-oxidase-like 1, 2 and 4 and transglutaminase 2 were found. Western blotting confirmed the upregulation of lysyl hydroxylase 2 in the ECM. Increased transglutaminase activity in TGF\u03b2-1 treated ECM was revealed from a cell-based assay. We employed a mass spectrometry-based method to identify alterations in the ECM cross-linking pattern caused by TGF\u03b2-1. Cross-linking sites were identified in collagens I and V, fibrinogen and fibronectin. One cross-linking site in fibrinogen alpha was found only in TGF\u03b2-treated samples. In conclusion, we have mapped novel cross-links between ECM proteins and demonstrated that activation of TGF\u03b2 signalling in cultured dermal fibroblasts upregulates multiple cross-linking enzymes in the ECM.<\/jats:p>","DOI":"10.3390\/ijms22030984","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T04:10:48Z","timestamp":1611115848000},"page":"984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["TGF\u03b2-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts"],"prefix":"10.3390","volume":"22","author":[{"given":"Mariya E.","family":"Semkova","sequence":"first","affiliation":[{"name":"Institute for Liver and Digestive Health, Division of Medicine, University College London, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-7564","authenticated-orcid":false,"given":"J. Justin","family":"Hsuan","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Health, Division of Medicine, University College London, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nm0511-552","article-title":"Scraping fibrosis: Expressway to the core of fibrosis","volume":"17","author":"Mehal","year":"2011","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-7113-8_1","article-title":"Human Fibrotic Diseases: Current Challenges in Fibrosis Research","volume":"1627","author":"Rosenbloom","year":"2017","journal-title":"Methods Mol. 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