1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone:: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport
1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone:: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport
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DOI：
10.1152/ajpgi.00243.2005
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发表时间：
2005-12-01
影响因子：
4.5
通讯作者：
Ghishan, FK
中科院分区：
文献类型：
--
作者：
Kolek, OI;Hines, ER;Ghishan, FK
成纤维细胞生长因子（FGF）23是一种磷酸尿激素，可降低循环1 α，25-二羟基维生素D（3）[1，25（OH）（2）D-3]和高血压性低磷酸盐血症，这两种激素均会导致佝偻病/骨软化症。最近已经显示，在用肾1，25（OH）（2）D-3激素治疗后，血清FGF 23增加，表明1，25（OH）（2）D-3通过诱导FGF 23负反馈控制其水平。为了确定1，25（OH）2D 3增加循环FGF 23的组织来源和分子机制，我们将1，25（OH）（2）D-3施用给C57 BL/6小鼠。在24小时内，这些小鼠显示出血清免疫反应性FGF 23的显著升高，骨中FGF 23 mRNA的表达被1，25（OH）（2）D-3显著上调，但在其他几个组织中没有影响。此外，我们用1，25（OH）（2）D-3处理大鼠UMR-106成骨细胞样细胞，实时PCR分析显示FGF 23 mRNA浓度的剂量和时间依赖性刺激。在10（-7）M 1，25（OH）（2）D-3处理24小时后，FGF 23 mRNA的最大增加为1，024倍，但早在1，25（OH）（2）D-3处理后4小时就观察到统计学显著差异。此外，使用放线菌素D或放线菌酮共处理，我们观察到，1，25（OH）（2）D-3的FGF 23基因表达的调节发生在转录水平上，可能通过核维生素D受体，并依赖于中间转因子的合成。这些结果表明，骨是FGF 23表达的主要部位，并且是1，25（OH）（2）D-3给药或生理上调后循环FGF 23的来源。我们的数据还建立了成骨细胞中1，25（OH）（2）D-3对FGF 23的诱导作用，作为这两种激素之间的反馈回路，完成了介导磷酸盐稳态的肾-肠-骨轴。
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.