| 16020653 |
Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK: 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005 Dec;289(6):G1036-42. Epub 2005 Jul 14.
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that decreases circulating 1alpha,25-dihydroxyvitamin D (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)(2) D (3) 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. |
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