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Although TGF\u03b2 is a central mediator of fibrosis, its pleiotropic physiological functions have limited the development of direct anti-fibrotic therapies, highlighting the need to identify context-specific regulators of this pathway. Matrix Gla Protein (MGP) is a vitamin K-dependent extracellular protein best known for inhibiting vascular calcification; however, its role in kidney fibrosis remains unknown. Here, we demonstrate that MGP expression is markedly upregulated in fibroblasts from fibrotic kidneys in mouse models of chronic kidney injury and in human CKD samples. Using inducible global and fibroblast-specific\n                    <jats:italic>Mgp<\/jats:italic>\n                    knockout mice, we show that\n                    <jats:italic>Mgp<\/jats:italic>\n                    deficiency attenuates renal fibrosis, suppresses fibroblast activation, and preserves kidney function following folic acid nephropathy and unilateral ureteral obstruction. Mechanistically, MGP promotes FMT and amplifies TGF\u03b2 receptor\/Smad3 signaling, whereas genetic or molecular inhibition of MGP blunts TGF\u03b2-driven fibroblast activation both in vivo and in vitro. We further identify phosphorylation and \u03b3-carboxylation as essential post-translational modifications required for the profibrotic activity of MGP. In addition, MGP interacts with bone morphogenetic protein-2 (BMP-2), reduces BMP-2 protein abundance, and counteracts BMP-2-mediated suppression of TGF\u03b2 signaling, thereby enhancing profibrotic responses. Collectively, these findings identify MGP as a previously unrecognized regulator of TGF\u03b2-dependent fibroblast activation and kidney fibrosis, supporting MGP as a potential fibroblast-associated target for future strategies aimed at limiting CKD progression.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00518-0","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T01:30:14Z","timestamp":1785979814000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Matrix Gla Protein is a novel regulator of TGF\u03b2\u2013dependent fibroblast activation and kidney fibrosis"],"prefix":"10.1186","volume":"7","author":[{"given":"Jonatan","family":"Barrera-Chimal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"L\u00f3pez-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Henley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeye","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Desjardins-Lecavalier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Costantino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Royal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn M.","family":"Agten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Borr\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Pichette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren A.","family":"Yuen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon J.","family":"Schurgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casimiro","family":"Gerarduzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"issue":"10518","key":"518_CR1","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/S0140-6736(25)01853-7","volume":"406","author":"Collaborators GBDCKD","year":"2025","unstructured":"Collaborators GBDCKD. 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