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Here we investigated how TGF-\u03b2 regulates expression of fibrous markers: Scleraxis, Fibromodulin and Adamtsl2. We showed that TGF-\u03b2 stimulated expression of Scleraxis mRNA by 2 h and Fibromodulin and Adamtsl2 mRNAs by 8 h of treatment. Regulation of Scleraxis by TGF-\u03b2 did not require new protein synthesis; however, protein synthesis was required for expression of Fibromodulin and Adamtsl2 indicating the necessity of an intermediate. We subsequently showed Scleraxis was a potential intermediate for TGF-\u03b2-regulated expression of Fibromodulin and Adamtsl2. The canonical effector Smad3 was not necessary for TGF-\u03b2-mediated regulation of Scleraxis. Smad3 was necessary for regulation of Fibromodulin and Adamtsl2, but not sufficient to super-induce expression with TGF-\u03b2 treatment. Next, the role of several noncanonical TGF-\u03b2 pathways were tested. We found that ERK1\/2 was activated by TGF-\u03b2 and required to regulate expression of Scleraxis, Fibromodulin, and Adamtsl2. Based on these results, we propose a model in which TGF-\u03b2 regulates Scleraxis via ERK1\/2 and then Scleraxis and Smad3 cooperate to regulate Fibromodulin and Adamtsl2. These results define a novel signaling mechanism for TGF\u03b2-mediated fibrous differentiation in sclerotome.<\/jats:p>","DOI":"10.1038\/s41598-020-78206-4","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T06:07:06Z","timestamp":1607321226000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Canonical and noncanonical TGF-\u03b2 signaling regulate fibrous tissue differentiation in the axial skeleton"],"prefix":"10.1038","volume":"10","author":[{"given":"Sade W.","family":"Clayton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga I.","family":"Ban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunren","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"78206_CR1","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.jpain.2008.10.012","volume":"10","author":"Y Takahashi","year":"2009","unstructured":"Takahashi, Y., Ohtori, S. & Takahashi, K. 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