{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T02:54:15Z","timestamp":1794020055604,"version":"4.8.0"},"reference-count":41,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Ehlers\u2013Danlos Society","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]},{"name":"The Ehlers\u2013Danlos Society","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]},{"name":"The Ehlers\u2013Danlos Society","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]},{"name":"The Ehlers\u2013Danlos Society","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]},{"name":"Molecular Studies in hEDS and HSD","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]},{"name":"Molecular Studies in hEDS and HSD","award":["2018.02c.LOI.26"],"award-info":[{"award-number":["2018.02c.LOI.26"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypermobile Ehlers\u2013Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS\/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.<\/jats:p>","DOI":"10.3390\/cells11244040","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T02:54:21Z","timestamp":1670986461000},"page":"4040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers\u2013Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-2495","authenticated-orcid":false,"given":"Marco","family":"Ritelli","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\/0000-0002-1760-5079","authenticated-orcid":false,"given":"Nicola","family":"Chiarelli","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\/0000-0002-1545-4801","authenticated-orcid":false,"given":"Valeria","family":"Cinquina","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\/0000-0003-0197-8927","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":"Valeria","family":"Bertini","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 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":[[2022,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/s41572-020-0194-9","article-title":"The Ehlers\u2013Danlos syndromes","volume":"6","author":"Malfait","year":"2020","journal-title":"Nat. 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