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

Abstract

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.

Insight into mechanism of tumor-related bone disease

Diagnosis and treatment of a rare tumor-induced bone disease could be improved by new insight into its pathogenesis. Thomas Clemens from Johns Hopkins School of Medicine and colleagues studied the molecular mechanisms that cause non-malignant tumors to release high levels of fibroblast growth factor 23 (FGF23), which in turn cause tumor-induced osteomalacia (TIO), a softening of bones due to excessive phosphate excretion. They focused on the role of the HIF-1α protein, a gene regulator that is involved in similar FGF23-dependent phosphate wasting diseases. In cells from the tumors of patients with TIO, HIF-1α expression was higher than normal, and its binding to DNA switched on expression of FGF23. The researchers concluded that HIF-1α directly regulates the expression of FGF23 in tumors, suggesting new opportunities for the development of diagnostic tests and treatment for TIO.

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