{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T22:57:58Z","timestamp":1776293878161,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundaci\u00f3 La Marat\u00f3 de TV3","award":["202038"],"award-info":[{"award-number":["202038"]}]},{"name":"Fundaci\u00f3 La Marat\u00f3 de TV3","award":["RYC2021-030866-1"],"award-info":[{"award-number":["RYC2021-030866-1"]}]},{"name":"Spanish Ministry of Science","award":["202038"],"award-info":[{"award-number":["202038"]}]},{"name":"Spanish Ministry of Science","award":["RYC2021-030866-1"],"award-info":[{"award-number":["RYC2021-030866-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGF\u03b21 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGF\u03b21 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNF\u03b1 and IL6 produced negligible levels of Activin A and TGF\u03b21 in both cell groups. We present for the first time TGF\u03b21 as a triggering factor of Activin A production in FOP. As TGF\u03b21 can promote the induction of the main driver of FOP, TGF\u03b21 could also be considered a possible therapeutic target in FOP treatment.<\/jats:p>","DOI":"10.3390\/ijms24032299","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:53:18Z","timestamp":1674618798000},"page":"2299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5035-9199","authenticated-orcid":false,"given":"Ruben D.","family":"de Ruiter","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Endocrinology Section, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9367-5730","authenticated-orcid":false,"given":"Lisanne E.","family":"Wisse","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-374X","authenticated-orcid":false,"given":"Ton","family":"Schoenmaker","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, 1012 WX Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maqsood","family":"Yaqub","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"S\u00e1nchez-Duffhues","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology, Leiden University Medical Centre, Universiteit Leiden, 2311 EZ Leiden, The Netherlands"},{"name":"Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5399-676X","authenticated-orcid":false,"given":"E. Marelise W.","family":"Eekhoff","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Endocrinology Section, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitra","family":"Micha","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1750-1172-6-80","article-title":"Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects","volume":"6","author":"Pignolo","year":"2011","journal-title":"Orphanet J. 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