FGF‐23 has arisen as an early biomarker of renal dysfunction, but at the onset of chronic kidney disease (CKD), data suggest that FGF‐23 may be produced independently of the parathyroid hormone (PTH), 1,25(OH)₂‐vitamin D₃ signaling axis. Iron status is inversely correlated to the level of circulating FGF‐23, and improvement in iron bioavailability within patients correlates with a decrease in FGF‐23. Alternately, recent evidence also supports a regulatory role of inflammatory cytokines in the modulation of FGF‐23 expression. To determine the identity of the signal from the kidney‐inducing upregulation of osteocytic FGF‐23 at the onset of CKD, we utilized a mouse model of congenital CKD that fails to properly mature the glomerular capillary tuft. We profiled the sequential presentation of indicators of renal dysfunction, phosphate imbalance, and iron bioavailability and transport to identify the events that initiate osteocytic production of FGF‐23 during the onset of CKD. We report here that elevations in circulating intact‐FGF‐23 coincide with the earliest indicators of renal dysfunction (P14), and precede changes in serum phosphate or iron homeostasis. Serum PTH was also not changed within the first month. Instead, production of the inflammatory protein IL‐1β from the kidney and systemic elevation of it in the circulation matched the induction of FGF‐23. IL‐1β's ability to induce FGF‐23 was confirmed on bone chips in culture and within mice in vivo. Furthermore, neutralizing antibody to IL‐1β blocked FGF‐23 expression in both our congenital model of CKD and a second nephrotoxic serum‐mediated model. We conclude that early CKD resembles a situation of primary FGF‐23 excess mediated by inflammation. These findings do not preclude that altered mineral availability or anemia can later modulate FGF‐23 levels but find that in early CKD they are not the driving stimulus for the initial upregulation of FGF‐23. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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IL-1β 在小鼠慢性肾病发作时驱动 FGF-23 的产生。

FGF-23 已成为肾功能障碍的早期生物标志物，但在慢性肾病 (CKD) 发作时，数据表明 FGF-23 可能独立于甲状旁腺激素 (PTH)、1,25(OH) _{2 产生}-维生素D ₃信号轴。铁状态与循环 FGF-23 的水平呈负相关，患者体内铁生物利用度的提高与 FGF-23 的减少相关。或者，最近的证据也支持炎症细胞因子在调节 FGF-23 表达中的调节作用。为了确定 CKD 发病时肾诱导骨细胞 FGF-23 上调的信号的身份，我们使用了先天性 CKD 小鼠模型，该模型无法正确成熟肾小球毛细血管簇。我们分析了肾功能障碍、磷酸盐失衡以及铁生物利用度和转运指标的顺序呈现，以确定在 CKD 发作期间启动 FGF-23 骨细胞生成的事件。我们在此报告，循环完整 FGF-23 的升高与肾功能障碍的最早指标 (P14) 一致，并先于血清磷酸盐或铁稳态的变化。血清 PTH 在第一个月内也没有变化。相反，来自肾脏的炎症蛋白 IL-1β 的产生及其在循环中的全身升高与 FGF-23 的诱导相匹配。IL-1β 诱导 FGF-23 的能力在培养的骨片和小鼠体内得到证实。此外，针对 IL-1β 的中和抗体在我们的先天性 CKD 模型和第二种肾毒性血清介导模型中均阻断了 FGF-23 的表达。我们得出结论，早期 CKD 类似于炎症介导的原发性 FGF-23 过量的情况。这些发现并不排除矿物质可用性改变或贫血可以在以后调节 FGF-23 水平，但发现在早期 CKD 中，它们不是 FGF-23 初始上调的驱动刺激。© 2020 美国骨与矿物研究学会。