Journal Article

The hypoxia-inducible factor-lα activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

Qian Zhang Michele Doucet Ryan E Tomlinson Xiaobin Han L Darryl Quarles Michael T Collins Thomas L Clemens

2016

Overview

Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la 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-la 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-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor

• Subject: HIF-1α / 低磷血症 / 成纤维细胞生长因子 / 生产 / 缺氧诱导因子-1α / 肿瘤组织 / 转录激活 / 软化