Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, 190 Longwood Avenue, Boston, MA 02115, USA.
Expert Opin Ther Pat. 2010 Jul;20(7):981-5. doi: 10.1517/13543771003774100.
The molecular interaction of fibroblast growth factor 23 (FGF23) and klotho is essential for physiologic regulation of phosphate balance. In the absence of klotho, the FGF23 protein cannot exert its physiologic functions, as demonstrated by in vivo mouse genetic studies. Bioactive FGF23 protein loses its phosphate lowering effects in genetically modified mice with no klotho activity. The FGF23-klotho system not only affects phosphate homeostasis but can also influence parathyroid hormone (PTH) and vitamin D activities. Dysregulation of the FGF23-klotho system is noted in a number of human acquired and genetic diseases, including chronic kidney disease. Vitamin D is a strong inducer of both FGF23 and klotho expression, while FGF23 can suppress the renal expression of 1alpha(OH)ase to reduce 1,25(OH)(2)D activity. An understanding of the complex interactions of phosphate, vitamin D and PTH with the FGF23-klotho system has paved the way to explore the therapeutic benefits of modulating the FGF23-klotho system in diseases associated with abnormal mineral ion balance. The patent (WO2009095372) under discussion proposes using fusion polypeptides to manipulate the FGF23-klotho system.
成纤维细胞生长因子 23（FGF23）与 klotho 的分子相互作用对于磷酸盐平衡的生理调节至关重要。在没有 klotho 的情况下，如体内小鼠遗传研究所示，FGF23 蛋白无法发挥其生理功能。在没有 klotho 活性的基因修饰小鼠中，生物活性 FGF23 蛋白会失去其降低磷酸盐的作用。FGF23-klotho 系统不仅影响磷酸盐的动态平衡，还可以影响甲状旁腺激素（PTH）和维生素 D 的活性。在许多人类获得性和遗传性疾病中，包括慢性肾脏病，都注意到 FGF23-klotho 系统的失调。维生素 D 是 FGF23 和 klotho 表达的强烈诱导剂，而 FGF23 可以抑制肾脏 1α(OH)酶的表达，从而降低 1,25(OH)（2）D 的活性。对磷酸盐、维生素 D 和 PTH 与 FGF23-klotho 系统之间复杂相互作用的理解，为探索调节与异常矿物质离子平衡相关疾病中的 FGF23-klotho 系统的治疗益处铺平了道路。正在讨论的专利（WO2009095372）提议使用融合多肽来操纵 FGF23-klotho 系统。
