University of Zurich, Institute of Physiology, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.
Pflugers Arch. 2018 Oct;470(10):1569-1582. doi: 10.1007/s00424-018-2171-7. Epub 2018 Jul 2.
Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH) vitamin D metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH) vitamin D, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH) vitamin D are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH) D levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71 erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH) vitamin D levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism.
成纤维细胞生长因子 23（FGF23）是调节磷酸盐和 1,25（OH）维生素 D 代谢的主要内分泌激素，主要由骨细胞产生。其产生受多种因素上调，包括 1,25（OH）维生素 D、高膳食磷酸盐摄入和甲状旁腺激素（PTH）。最近，铁缺乏和缺氧被认为是 FGF23 的另外调节因子，并且证明了促红细胞生成素（EPO）的作用。然而，EPO 对 FGF23 的调节及其对磷酸盐和 1,25（OH）维生素 D 的影响尚不完全清楚。在这里，我们证明了重组人促红细胞生成素（rhEPO）在健康人体中的急性给药增加了 FGF23 的 C 端片段（C 端 FGF23），但不增加完整的 FGF23（iFGF23）。在小鼠中，rhEPO 可在 24 小时内急性刺激 C 端 FGF23，但在 4 天后才刺激 iFGF23，对 PTH 和血浆磷酸盐无影响。肾脏 1,25（OH）D 水平和 αklotho 表达在 4 天后降低。rhEPO 在骨髓中诱导 FGF23 mRNA，但不在骨中诱导，骨髓中 CD71 红细胞前体中的 FGF23 染色增加。转基因小鼠中 EPO 的慢性升高增加了 iFGF23。最后，重组 FGF23 的急性注射降低了肾脏 EPO mRNA 的表达。我们的数据表明，FGF23 水平在小鼠中的刺激主要影响 1,25（OH）维生素 D 水平和代谢。在人类中，EPO 主要与 FGF23 的 C 端片段相关；在小鼠中，EPO 对两种 FGF23 形式具有时间依赖性作用。EPO 和 FGF23 可能形成一个反馈环，控制和连接红细胞生成和矿物质代谢。
