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The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

查看全文 作　　者：Qian [1]Zhang;Michele [1]Doucet;Ryan E [1]Tomlinson;Xiaobin [2]Han;L Darryl [2]Quarles;Michael T [3]Collins;Thomas L [1,4]Clemens 高影响力作者 机构地区：[1]Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD, USA;[2]Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA;[3]Skeletal Clinical Studies Unit, craniofacial and Skeletal Diseases Branch, National Institutes of Health,Bethesda, MD, USA;[4]Baltimore Veterans Administration Medical Center, Baltimore, MD, USA高影响力机构 出　　处：《Bone Research》索引2016年第4卷第2期,共6页高影响力期刊 基　　金：supported by NIH grants AR049510 (TLC) and AR045955 (LDQ) 摘　　要：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 spindleshaped 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. 关 键 词：成纤维细胞生长因子 缺氧诱导因子-1Α 肿瘤组织 转录激活 生产 HIF-1α 软化 低磷血症
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