Department of Orthopaedic Surgery, Johns Hopkins University , Baltimore, MD, USA.
Department of Medicine, University of Tennessee Health Science Center , Memphis, TN, USA.
Bone Res. 2016 Jul 5;4:16011. doi: 10.1038/boneres.2016.11. eCollection 2016.
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-1α (HIF-1α) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1α 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-1α 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-1α protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1α expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1α inhibitors decreased HIF-1α and FGF23 protein accumulation and inhibited HIF-1α-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1α consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1α inhibitor. These results show for the first time that HIF-1α is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1α activity in TIO contributes to the aberrant FGF23 production in these patients.
肿瘤相关性骨软化症（TIO）是一种罕见的副瘤综合征，其特征为非恶性间叶肿瘤异位产生成纤维细胞生长因子 23（FGF23），导致磷酸盐丢失和骨折。最近的研究表明，缺氧诱导因子-1α（HIF-1α）在其他由 FGF23 升高引起的磷酸盐丢失疾病中起作用，包括 X 连锁低磷血症性佝偻病和常染色体显性低磷血症。在这里，我们提供的证据表明，HIF-1α 通过转录激活其启动子介导 TIO 中的异常 FGF23。对从患有明确 TIO 的患者切除的磷酸化解质肿瘤进行免疫组织化学研究表明，HIF-1α 和 FGF23 在紧邻血管的纺锤形细胞中存在共定位。培养的肿瘤组织产生高水平的完整 FGF23，并显示 HIF-1α 蛋白表达增加。用 HIF-1α 表达构建体转染 MC3T3-E1 和 Saos-2 细胞诱导 FGF23 报告基因构建体的活性。先用 HIF-1α 抑制剂预处理肿瘤器官培养物可减少 HIF-1α 和 FGF23 蛋白积累，并抑制转染细胞中 HIF-1α 诱导的荧光素酶报告基因活性。染色质免疫沉淀分析证实了与 FGF23 启动子近端的 HIF-1α 共有序列结合，该结合在使用 HIF-1α 抑制剂处理后被消除。这些结果首次表明 HIF-1α 是 FGF23 的直接转录激活子，并表明 TIO 中 HIF-1α 活性的上调导致这些患者中异常的 FGF23 产生。
