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HORMONES AND SIGNALING
,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport
Departments of 1Pediatrics, 2Orthopedic Surgery, and 3Biochemistry and Molecular Biophysics, College of Medicine, Steele Children's Research Center, University of Arizona, Tucson, Arizona
Submitted 25 May 2005 ; accepted in final form 8 July 2005
Fibroblast growth factor (FGF)23 is a phosphaturic hormone that decreases circulating 1
,25-dihydroxyvitamin D3 [1,25(OH)2D3] 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)2D3 hormone, suggesting that 1,25(OH)2D3 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)2D3 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)2D3, but there was no effect in several other tissues. Furthermore, we treated rat UMR-106 osteoblast-like cells with 1,25(OH)2D3, 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)2D3 after 24-h treatment, but statistically significant differences were observed as early as 4 h after 1,25(OH)2D3 treatment. In addition, using cotreatment with actinomycin D or cycloheximide, we observed that 1,25(OH)2D3 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)2D3 administration or physiological upregulation. Our data also establish FGF23 induction by 1,25(OH)2D3 in osteoblasts as a feedback loop between these two hormones that completes a kidney-intestine-bone axis that mediates phosphate homeostasis.
fibroblast growth factor 23; gene regulation
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