Author:
Kolek Olga I.,Hines Eric R.,Jones Marci D.,LeSueur Loren K.,Lipko Maciej A.,Kiela Pawel R.,Collins James F.,Haussler Mark R.,Ghishan Fayez K.
Abstract
Fibroblast growth factor (FGF)23 is a phosphaturic hormone that decreases circulating 1α,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)2D3hormone, suggesting that 1,25(OH)2D3negatively feedback controls its levels by inducing FGF23. To establish the tissue of origin and the molecular mechanism by which 1,25(OH)2D3increases circulating FGF23, we administered 1,25(OH)2D3to 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 10−7M 1,25(OH)2D3after 24-h treatment, but statistically significant differences were observed as early as 4 h after 1,25(OH)2D3treatment. In addition, using cotreatment with actinomycin D or cycloheximide, we observed that 1,25(OH)2D3regulation 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)2D3administration or physiological upregulation. Our data also establish FGF23 induction by 1,25(OH)2D3in osteoblasts as a feedback loop between these two hormones that completes a kidney-intestine-bone axis that mediates phosphate homeostasis.
Publisher
American Physiological Society
Subject
Physiology (medical),Gastroenterology,Hepatology,Physiology
Cited by
353 articles.
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