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The accumulation of extracellular matrix impairs the contractility of muscle cells contributing to organ failure. Transforming growth factor \u03b2 (TGF-\u03b2) plays a pivotal role in fibrosis, activating pro-fibrotic gene programmes via phosphorylation of SMAD2\/3 transcription factors. However, the mechanisms that control de-phosphorylation of SMAD2 and SMAD3 (SMAD2\/3) have remained poorly characterized. Here, we show that tissue non-specific alkaline phosphatase (TNAP, also known as ALPL) is highly upregulated in hypertrophic hearts and in dystrophic skeletal muscles, and that the abrogation of TGF-\u03b2 signalling in TNAP-positive cells reduces vascular and interstitial fibrosis. We show that TNAP colocalizes and interacts with SMAD2. The TNAP inhibitor MLS-0038949 increases SMAD2\/3 phosphorylation, while TNAP overexpression reduces SMAD2\/3 phosphorylation and the expression of downstream fibrotic genes. Overall our data demonstrate that TNAP negatively regulates TGF-\u03b2 signalling and likely represents a mechanism to limit fibrosis.<\/jats:p>","DOI":"10.1242\/jcs.234948","type":"journal-article","created":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T08:55:15Z","timestamp":1562662515000},"source":"Crossref","is-referenced-by-count":18,"title":["TNAP limits TGF-\u03b2-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2\/3 transcription factors"],"prefix":"10.1242","volume":"132","author":[{"given":"Benedetta","family":"Arn\u00f2","sequence":"first","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"},{"name":"Medicines Discovery Catapult 2 , Mereside, Alderley Edge SK104TG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-4086","authenticated-orcid":false,"given":"Francesco","family":"Galli","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7849-2055","authenticated-orcid":false,"given":"Urmas","family":"Roostalu","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"},{"name":"Gubra H\u00f8rsholm Kongevej 3 \u2008 11B 2970 H\u00f8rsholm , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashar M.","family":"Aldeiri","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"},{"name":"King's College Hospital 4 , Denmark Hill, London SE5 9RS , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuaki","family":"Miyake","sequence":"additional","affiliation":[{"name":"York University 5 Department of Biology , , Toronto, ON, M3J 1P3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Albertini","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"},{"name":"TIGET-HSR, Ospedale San Raffele 6 , Via Olgettina 60, 20132 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laricia","family":"Bragg","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhpal","family":"Prehar","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre, The University of Manchester 7 Division of Cardiovascular Sciences , , Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"McDermott","sequence":"additional","affiliation":[{"name":"York University 5 Department of Biology , , Toronto, ON, M3J 1P3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Cartwright","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre, The University of Manchester 7 Division of Cardiovascular Sciences , , Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5863-9593","authenticated-orcid":false,"given":"Giulio","family":"Cossu","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health , , Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,8,8]]},"reference":[{"key":"2024061318311418500_JCS234948C1","first-page":"677","article-title":"Connective tissue changes and physical properties of developing and ageing skeletal muscle","volume":"139","author":"Alnaqeeb","year":"1984","journal-title":"J. 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