Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka 594-1101, Japan.
Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka 594-1101, Japan.
Bone. 2022 Aug;161:116430. doi: 10.1016/j.bone.2022.116430. Epub 2022 May 13.
Serum inorganic phosphate (Pi) levels are higher in children than in adults; however, the underlying mechanisms remain unclear. Therefore, we herein attempted to elucidate the mechanisms altering Pi metabolism from youth to adulthood using 4-week-old (young) and 12-week-old (adult) mice. Despite higher serum Pi levels, serum fibroblast growth factor 23 (FGF23) levels were lower in young mice, and the amount of FGF23 in bone tended to increase from youth to adulthood. Increases in serum FGF23 levels during growth were associated with the up- and down-regulation of the renal expression of Cyp24a1 encoding vitamin D-24-hydroxylase and Slc34a3 encoding the type IIc sodium/phosphate (Na/Pi) co-transporter, respectively, suggesting an enhancement in the FGF23-mediated bone-kidney axis from youth to adulthood. We then isolated osteoblasts and osteocytes from young and adult mice and compared the expression of genes involved in Pi metabolism and/or mineralization. In contrast to the growth-related increase in Fgf23 expression, the expression of some genes, including the dentin matrix protein 1 (Dmp1) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex) markedly decreased from youth to adulthood. The down-regulation of Dmp1 and Phex may contribute to growth-related increases in FGF23. The responses of isolated osteoblasts and osteocytes to high Pi levels also markedly differed between young and adult mice. Treatment of isolated osteocytes with high Pi increased the production of FGF23 in adult mice but not in young mice. These results indicate a close relationship between skeletal changes from youth to adulthood and an alteration in Pi metabolism, and provide insights into the mechanisms by which osteoblasts and osteocytes maintain Pi homeostasis.
血清无机磷 (Pi) 水平在儿童中高于成人；然而，其潜在机制尚不清楚。因此，我们试图使用 4 周龄（幼年期）和 12 周龄（成年期）的小鼠来阐明从青年到成年期改变 Pi 代谢的机制。尽管血清 Pi 水平较高，但幼鼠的血清成纤维细胞生长因子 23 (FGF23) 水平较低，且骨中 FGF23 的含量趋于从青年到成年期增加。生长过程中血清 FGF23 水平的升高与 Cyp24a1（编码维生素 D-24-羟化酶）和 Slc34a3（编码 IIc 型钠/磷 (Na/Pi) 共转运体）的肾表达的上调和下调分别相关，提示 FGF23 介导的从青年到成年期的骨骼-肾脏轴增强。然后，我们从小鼠的幼年期和成年期分离出成骨细胞和破骨细胞，并比较了参与 Pi 代谢和/或矿化的基因的表达。与 Fgf23 表达的生长相关增加相反，一些基因的表达，包括牙本质基质蛋白 1 (Dmp1) 和 X 染色体同源的内肽酶磷调节基因 (Phex)，从幼年期到成年期明显下降。Dmp1 和 Phex 的下调可能有助于 FGF23 的生长相关增加。分离的成骨细胞和破骨细胞对高 Pi 水平的反应在幼年期和成年期的小鼠之间也有明显差异。用高 Pi 处理分离的破骨细胞会增加成年小鼠而不是幼年小鼠中 FGF23 的产生。这些结果表明，从青年到成年期骨骼变化与 Pi 代谢的改变密切相关，并为成骨细胞和破骨细胞维持 Pi 稳态的机制提供了新的见解。
