{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:57:09Z","timestamp":1791644229109,"version":"4.3.4"},"reference-count":60,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011666","name":"The Ehlers-Danlos Society","doi-asserted-by":"publisher","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}],"id":[{"id":"10.13039\/100011666","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011666","name":"The Ehlers-Danlos Society","doi-asserted-by":"publisher","award":["Molecular Studies in hEDS and HSD $1 Million Grant"],"award-info":[{"award-number":["Molecular Studies in hEDS and HSD $1 Million Grant"]}],"id":[{"id":"10.13039\/100011666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients\u2019 phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients\u2019 quality of life and alleviate their disabilities.<\/jats:p>","DOI":"10.3390\/cells10113236","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T08:29:17Z","timestamp":1637310557000},"page":"3236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1760-5079","authenticated-orcid":false,"given":"Nicola","family":"Chiarelli","sequence":"first","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-8927","authenticated-orcid":false,"given":"Nicoletta","family":"Zoppi","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Venturini","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-728X","authenticated-orcid":false,"given":"Daniele","family":"Capitanio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2996-6912","authenticated-orcid":false,"given":"Cecilia","family":"Gelfi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, 20090 Milan, Italy"},{"name":"IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-2495","authenticated-orcid":false,"given":"Marco","family":"Ritelli","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3105-5990","authenticated-orcid":false,"given":"Marina","family":"Colombi","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers\u2013Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. 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