FGF23 Actions on Target Tissues-With and Without Klotho.
FGF23 Actions on Target Tissues-With and Without Klotho.
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DOI：
10.3389/fendo.2018.00189
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发表时间：
2018
影响因子：
5.2
通讯作者：
Faul C
中科院分区：
文献类型：
--
作者：
Richter B;Faul C
成纤维细胞生长因子（FGF） 23是一种磷酸化激素，其对靶组织的生理作用是由FGF受体（FGFR）和klotho介导的，klotho作为一种共受体，增加了FGF23对FGFR的结合亲和力。FGF23通过刺激肾脏和甲状旁腺中的FGFR/klotho复合物，分别减少肾脏对磷酸盐的摄取和甲状旁腺激素的分泌，从而成为磷酸盐代谢的关键调节剂。最近，研究表明FGF23也可以靶向缺乏klotho的细胞类型。这种非传统的信号事件以fgfr依赖的方式发生，但涉及其他下游信号通路，而不是“经典”表达kloho的靶器官。似乎klotho独立的信号机制仅在高FGF23浓度存在时被激活，并导致病理细胞变化。因此，有假设认为，在慢性肾病患者中发现的FGF23循环水平的大量升高，通过靶向缺乏klotho的细胞和组织，导致相关病理。这包括心脏肥大和纤维化的诱导，肝脏炎症细胞因子表达的升高，以及中性粒细胞募集的抑制。在这里，我们描述了FGF23在缺乏klotho的组织中引起的信号和细胞事件，并讨论了FGF23作为一种具有广泛病理作用的激素的潜在作用。由于klotho的可溶性形式可以作为FGF23的循环共受体，我们还讨论了可溶性klotho对FGF23介导的信号传导的潜在抑制作用，这可能-至少部分支持klotho的多效组织保护功能。
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.
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