Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span.
Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span.
复制标题
骨骼肌FGFR1信号传导对于通过FGF 23调节血清磷酸盐水平和正常寿命是必需的。
DOI：
10.1016/j.bbrep.2021.101107
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发表时间：
2021-09
影响因子：
2.7
通讯作者：
Fukumoto S
中科院分区：
文献类型：
--
作者：
Takashi Y;Sawatsubashi S;Endo I;Ohnishi Y;Abe M;Matsuhisa M;Kawanami D;Matsumoto T;Fukumoto S
骨产生的成纤维细胞生长因子（FGF） 23是调节血清磷酸盐水平的主要激素。需要严格调节血清FGF23以维持血清磷酸盐在一个狭窄的范围内。因此，我们假设骨具有某种磷酸盐感应机制来调节FGF23的产生。之前我们发现细胞外磷酸盐诱导FGF受体1 （FGFR1）的磷酸化，FGFR1信号传导调节Galnt3的表达，其产物在体外增加FGF23的产生。在本研究中，我们展示了FGFR1在体内调节FGF23生成和血清磷酸盐水平中的重要性。我们通过交叉Ocn-Cre和固定的Fgfr1小鼠系，产生了晚期成骨细胞/骨细胞特异性Fgfr1敲除小鼠（Fgfr1fl/fl; ocfrre /+）。我们评估了血清磷酸盐和FGF23水平，骨中Galnt3的表达，体重和寿命。选择性消融Fgfr1终止了高磷酸盐饮食中血清活性全长FGF23的增加和骨中Galnt3表达的增强。与对照组小鼠相比，这些小鼠表现出更明显的高磷血症。此外，用对照饮食喂养的小鼠在23周龄后体重下降，寿命缩短。这些结果揭示了FGFR1信号在磷酸盐代谢和正常寿命中的新意义。
Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.
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影响因子：
3.3
作者：
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