Center of Calcium and Bone Research, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Am J Physiol Endocrinol Metab. 2012 Apr 15;302(8):E903-13. doi: 10.1152/ajpendo.00620.2011. Epub 2012 Jan 24.
Despite being widely recognized as the important bone-derived phosphaturic hormone, whether fibroblast growth factor (FGF)-23 modulated intestinal calcium absorption remained elusive. Since FGF-23 could reduce the circulating level of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], FGF-23 probably compromised the 1,25(OH)₂D₃-induced intestinal calcium absorption. FGF-23 may also exert an inhibitory action directly through FGF receptors (FGFR) in the intestinal cells. Herein, we demonstrated by Ussing chamber technique that male mice administered 1 μg/kg 1,25(OH)₂D₃ sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1-4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH)₂D₃-induced calcium absorption in the duodenal tissues taken from the 1,25(OH)₂D₃-treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH)₂D₃ preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH)₂D₃-induced upregulation of TRPV5, TRPV6, and calbindin-D(9k), but not PMCA(1b) expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH)₂D₃-induced calcium absorption.
尽管成纤维细胞生长因子 23（fibroblast growth factor-23，FGF-23）被广泛认为是重要的骨源磷调节激素，但它是否调节肠道钙吸收仍不清楚。由于 FGF-23 可以降低循环 1,25-二羟维生素 D₃ [1,25(OH)₂D₃]水平，因此 FGF-23 可能会损害 1,25(OH)₂D₃诱导的肠道钙吸收。FGF-23 也可能通过肠道细胞中的成纤维细胞生长因子受体（fibroblast growth factor receptor，FGFR）直接发挥抑制作用。在此，我们通过 Ussing 室技术证明，每天 sc 给予雄性小鼠 1 μg/kg 1,25(OH)₂D₃ 共 3 天，可增加十二指肠钙吸收，而同时静脉注射重组鼠 FGF-23 则可消除这种作用。FGF-23 给药对基础上皮电特性（即短路电流、跨上皮电位差和电阻）没有影响。免疫组织化学证据表明，FGFR 同工型 1-4 的蛋白表达存在于小鼠十二指肠上皮细胞中，提示 FGF-23 可能对肠道有直接作用。这一发现得到了以下发现的支持：FGF-23 直接添加到 Ussing 室的浆膜腔中，并完全消除了从接受 1,25(OH)₂D₃ 处理的小鼠中取出的十二指肠组织中 1,25(OH)₂D₃ 诱导的钙吸收。然而，在没有预先注射 1,25(OH)₂D₃ 的情况下，直接暴露于 FGF-23 并不能降低十二指肠钙吸收。观察到的 FGF-23 作用是通过 MAPK/ERK、p38 MAPK 和 PKC 介导的。实时定量 PCR 进一步表明，FGF-23 降低了 1,25(OH)₂D₃ 诱导的 TRPV5、TRPV6 和钙结合蛋白-D9k 的上调，但不降低 PMCA1b 的表达。总之，除了作为磷调节激素外，FGF-23 还被证明是一种新型的钙调节激素，它直接作用于小鼠肠道，从而损害 1,25(OH)₂D₃ 诱导的钙吸收。
