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The objective of this study was to determine the mechanism by which TRPV4 channelopathy mutations cause skeletal dysplasia. The human TRPV4\n                    <jats:sub>V620I<\/jats:sub>\n                    channelopathy mutation was transfected into primary porcine chondrocytes and caused significant (2.6\u2010fold) up\u2010regulation of follistatin (\n                    <jats:italic>FST<\/jats:italic>\n                    ) expression levels. Pore altering mutations that prevent calcium influx through the channel prevented significant\n                    <jats:italic>FST<\/jats:italic>\n                    up\u2010regulation (1.1\u2010fold). We generated a mouse model of theTRPV4\n                    <jats:sub>V620I<\/jats:sub>\n                    mutation, and found significant skeletal deformities (\n                    <jats:italic>e.g<\/jats:italic>\n                    ., shortening of tibiae and digits, similar to the human disease brachyolmia) and increases in\n                    <jats:italic>Fst\/TRPV4<\/jats:italic>\n                    mRNA levels (2.8\u2010fold).\n                    <jats:italic>FST<\/jats:italic>\n                    was significantly up\u2010regulated in primary chondrocytes transfected with 3 different dysplasia\u2010causing TRPV4 mutations (2\u2010 to 2.3\u2010fold), but was not affected by an arthropathy mutation (1.1\u2010fold). Furthermore, FST\u2010loaded microbeads decreased bone ossification in developing chick femora (6%) and tibiae (11%). FST gene and protein levels were also increased 4\u2010fold in human chondrocytes from an individual natively expressing the TRPV4\n                    <jats:sub>T89I<\/jats:sub>\n                    mutation. Taken together, these data strongly support that up\u2010regulation of FST in chondrocytes by skeletal dysplasia\u2010inducing TRPV4 mutations contributes to disease pathogenesis.\u2014Leddy, H. A., McNulty, A. L., Lee, S. H., Rothfusz, N. E., Gloss, B., Kirby, M. L., Hutson, M. R., Cohn, D. H., Guilak, F., Liedtke, W. Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 28, 2525\u20132537 (2014).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.13-245936","type":"journal-article","created":{"date-parts":[[2014,2,28]],"date-time":"2014-02-28T00:50:04Z","timestamp":1393548604000},"page":"2525-2537","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations"],"prefix":"10.1096","volume":"28","author":[{"given":"Holly A.","family":"Leddy","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"McNulty","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Rothfusz","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Gloss","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret L.","family":"Kirby","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary R.","family":"Hutson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Cohn","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology University of California at Los Angeles Los Angeles California USA"},{"name":"Department of Orthopaedic Surgery Orthopaedic Hospital Research Center University of California at Los Angeles Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farshid","family":"Guilak","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Liedtke","sequence":"additional","affiliation":[{"name":"Department of Neurology Duke University Medical Center Durham North Carolina USA"},{"name":"Duke University Clinics for Pain and Palliative Care Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,2,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0470862580.ch10"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1201\/9781420005844.ch22","volume-title":"TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades","author":"Liedtke W.","year":"2006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"RE 1","DOI":"10.1126\/stke.2001.90.re1","article-title":"Physiology, phylogeny, and functions of the TRP superfamily of cation channels","volume":"2001","author":"Montell C.","year":"2001","journal-title":"Sci. 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