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The TGF\u03b2 pathway also plays a critical role in the development, organization and proliferation of the growth plate, although the exact mechanisms remain unclear. Skeletal phenotypes in Myhre syndrome overlap with processes regulated by the TGF\u03b2 pathway, including organization and proliferation of the growth plate and polarity of the chondrocyte. We used in vitro and in vivo models of Smad4 deficiency in chondrocytes to test the hypothesis that deregulated TGF\u03b2 signaling leads to aberrant extracellular matrix production and loss of chondrocyte polarity. Specifically, we evaluated growth plate chondrocyte polarity in tibiae of Col2-Cre+\/-;Smad4fl\/fl mice and in chondrocyte pellet cultures. In vitro and in vivo, Smad4 deficiency decreased aggrecan expression and increased MMP13 expression. Smad4-deficiency disrupts the balance of cartilage matrix synthesis and degradation, even though the sequential expression of growth plate chondrocyte markers was intact. Chondrocytes in Smad4 deficient growth plates also showed evidence of polarity defects, with impaired proliferation and ability to undergo the characteristic changes in shape, size and orientation as they differentiate from resting to hypertrophic chondrocytes. Therefore, we show that Smad4 controls chondrocyte proliferation, orientation, and hypertrophy and is important in regulating the extracellular matrix composition of the growth plate.<\/jats:p>","DOI":"10.1242\/bio.021436","type":"journal-article","created":{"date-parts":[[2017,2,7]],"date-time":"2017-02-07T01:40:24Z","timestamp":1486431624000},"source":"Crossref","is-referenced-by-count":12,"title":["Smad4 regulates growth plate matrix production and chondrocyte polarity"],"prefix":"10.1242","author":[{"given":"Amanda T.","family":"Whitaker","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, California, USA"},{"name":"Department of Orthopaedic Surgery, Nationwide Children\u2018s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellora","family":"Berthet","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cantu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology & Reproductive Sciences, Center for Reproductive Sciences, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, Department of Otolaryngology\u2013Head and Neck Surgery, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana J.","family":"Laird","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology & Reproductive Sciences, Center for Reproductive Sciences, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, Department of Otolaryngology\u2013Head and Neck Surgery, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-2897","authenticated-orcid":false,"given":"Tamara","family":"Alliston","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, California, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, Department of Otolaryngology\u2013Head and Neck Surgery, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"2021042423400401700_BIO021436C1","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1210\/endo.140.2.6513","article-title":"Determinants of spatial polarity in the growth plate","volume":"140","author":"Abad","year":"1999","journal-title":"Endocrinology"},{"key":"2021042423400401700_BIO021436C2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/78107","article-title":"Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2","volume":"25","author":"Afzal","year":"2000","journal-title":"Nat. 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