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Recent studies have implicated the hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1\u03b1 mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1\u03b1 and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1\u03b1 protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1\u03b1 expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1\u03b1 inhibitors decreased HIF-1\u03b1 and FGF23 protein accumulation and inhibited HIF-1\u03b1-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1\u03b1 consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1\u03b1 inhibitor. These results show for the first time that HIF-1\u03b1 is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1\u03b1 activity in TIO contributes to the aberrant FGF23 production in these patients.<\/jats:p>","DOI":"10.1038\/boneres.2016.11","type":"journal-article","created":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T13:44:34Z","timestamp":1468849474000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["The hypoxia-inducible factor-1\u03b1 activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia"],"prefix":"10.1038","volume":"4","author":[{"given":"Qian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Doucet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan E","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L Darryl","family":"Quarles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L","family":"Clemens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,5]]},"reference":[{"key":"BFboneres201611_CR1","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1023\/A:1010006811394","volume":"2","author":"MK Drezner","year":"2001","unstructured":"Drezner MK . 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