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The disease is characterized by joint contractures, muscle weakening and wasting, and heart conduction defects associated with dilated cardiomyopathy. Previous studies demonstrated the activation of fibrogenic molecules such as TGFbeta 2 and CTGF in preclinical models of EDMD2 and increased secretion of TGFbeta 2 in patient serum. A wide screening of patient cells suggested fibrosis, metabolism, and myogenic signaling as the most affected pathways in various EDMD forms. In this study, we show that alpha-smooth muscle actin-positive myofibroblasts are overrepresented in patient fibroblast cultures carrying EMD, LMNA, or SYNE2 mutations, and profibrotic miRNA-21 is upregulated. Upon CRISPR\/Cas correction of the mutated EMD or LMNA sequence in EDMD1 or EDMD2 fibroblasts, respectively, we observe a reduced expression of fibrogenic molecules. However, in patient myoblasts, neither fibrogenic proteins nor miRNA-21 were upregulated; instead, miRNA-21-5p was downregulated along with muscle-specific miRNA-133b and miRNA-206, which have a crucial role in muscle cell homeostasis. These observations suggest that the conversion of laminopathic fibroblasts into a profibrotic phenotype is a determinant of EDMD-associated muscle fibrosis, while miRNA-206-dependent defects of laminopathic myoblasts, including altered regulation of VEGF levels, contribute to muscle cell deterioration. Notably, our study provides a proof-of-principle for the application of gene correction to EDMD1 and EDMD2 and presents EDMD1 isogenic cells that exhibit an almost complete rescue of a disease-specific miRNA signature. These cells can be used as experimental models for studying muscular laminopathies.<\/jats:p>","DOI":"10.3390\/cells14171321","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T15:49:34Z","timestamp":1756309774000},"page":"1321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Profibrotic Molecules Are Reduced in CRISPR-Edited Emery\u2013Dreifuss Muscular Dystrophy Fibroblasts"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3737-2181","authenticated-orcid":false,"given":"Eleonora","family":"Cattin","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"},{"name":"Centre for Regenerative Medicine, \u201cStefano Ferrari\u201d University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5960-4157","authenticated-orcid":false,"given":"Elisa","family":"Schena","sequence":"additional","affiliation":[{"name":"CNR Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d, Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1395-1927","authenticated-orcid":false,"given":"Elisabetta","family":"Mattioli","sequence":"additional","affiliation":[{"name":"CNR Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d, Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6893-6372","authenticated-orcid":false,"given":"Stefania","family":"Marcuzzo","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8823-6821","authenticated-orcid":false,"given":"Silvia","family":"Bonanno","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-1524","authenticated-orcid":false,"given":"Paola","family":"Cavalcante","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4926-0411","authenticated-orcid":false,"given":"Federico","family":"Corradi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"},{"name":"Centre for Regenerative Medicine, \u201cStefano Ferrari\u201d University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6599-7193","authenticated-orcid":false,"given":"Daniela","family":"Benati","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"},{"name":"Centre for Regenerative Medicine, \u201cStefano Ferrari\u201d University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4177-8647","authenticated-orcid":false,"given":"Giorgia","family":"Farinazzo","sequence":"additional","affiliation":[{"name":"Neurology 4\u2014Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Neurology III\u2014Neuroalgology Unit, IRCCS \u201cC. 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