Kunert Svenja Kristin, Hartmann Hans, Haffner Dieter, Leifheit-Nestler Maren
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
J Bone Miner Metab. 2017 Mar;35(2):215-226. doi: 10.1007/s00774-016-0746-y. Epub 2016 Mar 26.
The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to mineral metabolism parameters in humans. In 39 children aged 0.3-16.8 years undergoing lumbar puncture for the exclusion of inflammatory neurological disease, sKlotho and FGF23 were investigated by Western blot analysis, followed by ELISA quantification in CSF and plasma. The percentage of intrathecal synthesis of both proteins was calculated by measuring both the expected and observed CSF/plasma ratios of sKlotho and FGF23. The secreted (KL1) and cleaved (KL1+KL2) isoforms of sKlotho, and FGF23 were clearly detected in CSF in all subjects, although protein levels were lower compared to those of plasma samples (each p < 0.01). The intrathecal percentage of CSF sKlotho and FGF23 synthesis amounted to 98 and 99 %, respectively. CSF sKlotho levels were higher in boys than in girls (p < 0.01), and correlated positively with plasma C-terminal FGF23 concentrations (p < 0.05) and standardized height (p < 0.01). Importantly, there were no significant correlations between plasma and CSF levels of sKlotho or FGF23. Plasma sKlotho as well as C-terminal and intact FGF23, respectively, were associated with parameters of mineral metabolism These results provide evidence that cleaved and secreted sKlotho and FGF23 are present in CSF, mainly derived from brain and affected by sex, height, and mineral metabolism parameters in children. Nevertheless, the absence of significant associations between plasma and CSF levels of Klotho and FGF23, respectively, suggest that the regulation of Klotho and FGF23 may be different between organs secreting these hormones into blood and CSF.
成纤维细胞生长因子（FGF）23/α-klotho轴是磷稳态和维生素D代谢的主要调节因子，但关于其在中枢神经系统中的作用的数据有限。在此，我们研究了脑脊液（CSF）和血浆中的可溶性α-klotho（sKlotho）、C末端以及完整的FGF23，以及它们与人类矿物质代谢参数的关系。在39名年龄在0.3至16.8岁之间因排除炎性神经系统疾病而接受腰椎穿刺的儿童中，通过蛋白质印迹分析研究了sKlotho和FGF23，随后在脑脊液和血浆中进行酶联免疫吸附测定（ELISA）定量。通过测量sKlotho和FGF23预期和观察到的脑脊液/血浆比率，计算两种蛋白质的鞘内合成百分比。在所有受试者的脑脊液中均清晰检测到sKlotho的分泌型（KL1）和裂解型（KL1+KL2）异构体以及FGF23，尽管蛋白质水平低于血浆样本（各p<0.01）。脑脊液sKlotho和FGF23合成的鞘内百分比分别为98%和99%。男孩脑脊液中的sKlotho水平高于女孩（p<0.01），且与血浆C末端FGF23浓度（p<0.05）和标准化身高（p<0.01）呈正相关。重要的是，血浆和脑脊液中sKlotho或FGF23水平之间无显著相关性。血浆sKlotho以及C末端和完整的FGF23分别与矿物质代谢参数相关。这些结果表明，裂解型和分泌型sKlotho以及FGF23存在于脑脊液中，主要来源于大脑，并受儿童性别、身高和矿物质代谢参数的影响。然而，血浆和脑脊液中Klotho和FGF23水平之间分别缺乏显著相关性，这表明在将这些激素分泌到血液和脑脊液的器官之间，Klotho和FGF23的调节可能有所不同。
