Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells

Fibroblast growth factor 23 (FGF23) has been shown to work as a phosphotropic hormone. Although FGF23 reduces the serum phosphate level, it has not been established that phosphate directly regulates FGF23 production. In this study, we investigated whether phosphate can enhance Fgf23 expression using the rat osteoblastic cell line UMR-106, which has been shown to express Fgf23 in response to 1,25-dihydroxyvitamin D [1,25(OH)2D]. Phosphate increased Fgf23 expression in a dose- and time-dependent manner in the presence of 1,25(OH)2D. Phosphate also increased Fgf23 promoter activity, but showed no effect on the half-life of Fgf23 messenger RNA. Phosphonoformic acid and PD98059, an inhibitor of MEK, inhibited the effects of phosphate on Fgf23 expression and promoter activity. In addition, phosphate enhanced production of reactive oxygen species (ROS) in UMR-106 cells, and hydrogen peroxide enhanced FGF23 production in a dose- and time-dependent manner. Hydrogen peroxide also enhanced Elk1 reporter activity, a target of the MEK-extracellular-signal-regulated kinase (ERK) pathway. Furthermore, the effect of phosphate on ROS production and Fgf23 expression was inhibited by apocynin, an inhibitor of NADPH oxidase. These results indicate that phosphate directly enhances Fgf23 transcription without affecting the stability of Fgf23 messenger RNA by stimulating NADPH-induced ROS production and the MEK-ERK pathway in UMR-106 cells.