1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone:: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that decreases circulating 1 alpha,25-dihydroxyvitaminD(3) [1,25(OH)(2)D-3] and elicits hypophosphatemia, both of which contribute to rickets/osteomalacia. It has been shown recently that serum FGF23 increases after treatment with renal 1,25(OH)(2)D-3 hormone, suggesting that 1,25(OH)(2)D-3 negatively feedback controls its levels by inducing FGF23. To establish the tissue of origin and the molecular mechanism by which 1,25( OH) 2D3 increases circulating FGF23, we administered 1,25(OH)(2)D-3 to C57BL/6 mice. Within 24 h, these mice displayed a dramatic elevation in serum immunoreactive FGF23, and the expression of FGF23 mRNA in bone was significantly upregulated by 1,25(OH)(2)D-3, but there was no effect in several other tissues. Furthermore, we treated rat UMR-106 osteoblast-like cells with 1,25(OH)(2)D-3, and real-time PCR analysis revealed a dose- and time-dependent stimulation of FGF23 mRNA concentrations. The maximum increase in FGF23 mRNA was 1,024-fold at 10(-7) M 1,25( OH)(2)D-3 after 24-h treatment, but statistically significant differences were observed as early as 4 h after 1,25(OH)(2)D-3 treatment. In addition, using cotreatment with actinomycin D or cycloheximide, we observed that 1,25(OH)(2)D-3 regulation of FGF23 gene expression occurs at the transcriptional level, likely via the nuclear vitamin D receptor, and is dependent on synthesis of an intermediary transfactor. These results indicate that bone is a major site of FGF23 expression and source of circulating FGF23 after 1,25(OH)(2)D-3 administration or physiological upregulation. Our data also establish FGF23 induction by 1,25(OH)(2)D-3 in osteoblasts as a feedback loop between these two hormones that completes a kidney-intestine-bone axis that mediates phosphate homeostasis.