Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
J Bone Miner Res. 2021 Feb;36(2):315-321. doi: 10.1002/jbmr.4195. Epub 2020 Nov 22.
Fibroblast growth factor 23 (FGF23) is a key phosphate- and vitamin D-regulating hormone. FGF23 circulates as an intact 251 amino acid protein or N- and C-terminal degradation products. Hormone activity resides in the intact molecule, but it has been suggested that high levels of the C-terminal protein can interfere with intact FGF23 (iFGF23) activity. New evidence points to involvement of the hypoxia-inducible factor (HIF)/erythropoietin (EPO)/iron pathway as important in FGF23 physiology. Exactly how this pathway regulates FGF23 is not clear. Various in vitro, in vivo, and clinical studies involving perturbations in this pathway at various points have yielded conflicting results. Many of these studies are complicated by the confounding, independent effect of renal insufficiency on FGF23. To gain insight into FGF23 physiology, we studied 8 patients with a rare paraganglioma/somatostatinoma syndrome who had elevated blood EPO levels as a result of somatic gain-of-function mutations in HIF2A (EPAS1) that stimulate tumoral EPO production. All patients had normal renal function. EPO levels varied; most were very elevated and highly correlated with C-terminal FGF23 (cFGF23) levels that were also markedly elevated. Blood phosphate and intact FGF23 levels were normal. These data from patients with normal renal function in whom HIF activation was the inciting event suggest a direct role of the HIF/EPO pathway in FGF23 transcription and translation. They also demonstrate that posttranslational regulation was finely tuned to maintain normal blood phosphate levels. Additionally, normal phosphate and intact FGF23 levels in the setting of markedly increased C-terminal FGF23 levels suggest intact FGF23 action is not attenuated by C-terminal FGF23. Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
成纤维细胞生长因子 23（FGF23）是一种关键的磷酸盐和维生素 D 调节激素。FGF23 作为一种完整的 251 个氨基酸蛋白或 N 端和 C 端降解产物循环。激素活性存在于完整的分子中，但有人认为高水平的 C 端蛋白可能会干扰完整的 FGF23（iFGF23）活性。新的证据表明，缺氧诱导因子（HIF）/促红细胞生成素（EPO）/铁途径的参与在 FGF23 生理学中很重要。确切的途径如何调节 FGF23 尚不清楚。各种涉及该途径在不同点的扰动的体外、体内和临床研究产生了相互矛盾的结果。这些研究中的许多都因肾功能不全对 FGF23 的干扰而变得复杂。为了深入了解 FGF23 的生理学，我们研究了 8 例罕见的副神经节瘤/生长抑素瘤综合征患者，这些患者由于 HIF2A（EPAS1）的体细胞获得性功能突变导致血液 EPO 水平升高，从而刺激肿瘤 EPO 产生。所有患者的肾功能均正常。EPO 水平变化；大多数非常高，与 C 端 FGF23（cFGF23）水平高度相关，cFGF23 水平也明显升高。血液磷酸盐和完整的 FGF23 水平正常。这些来自肾功能正常且 HIF 激活是激发事件的患者的数据表明，HIF/EPO 途径在 FGF23 的转录和翻译中具有直接作用。它们还表明，翻译后调节被精细地调整以维持正常的血液磷酸盐水平。此外，在明显增加的 C 端 FGF23 水平的情况下，正常的磷酸盐和完整的 FGF23 水平表明 C 端 FGF23 不会减弱完整的 FGF23 作用。2020 年出版。本文是美国政府的一项工作，在美国境内属于公有领域。由 Wiley Periodicals LLC 代表美国骨矿研究协会（ASBMR）出版的《骨与矿物研究杂志》。
