The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis

Abstract

Appropriate levels of phosphate in the body are maintained by the coordinated regulation of the bone-derived growth factor FGF23 and the membrane-bound protein Klotho. The endocrine actions of FGF23, in association with parathyroid hormone and vitamin D, mobilize sodium-phosphate cotransporters that control renal phosphate transport in proximal tubular epithelial cells. The availability of an adequate amount of Klotho is essential for FGF23 to exert its phosphaturic effects in the kidney. In the presence of Klotho, FGF23 activates downstream signaling components that influence the homeostasis of phosphate, whereas in the absence of this membrane protein, it is unable to exert such regulatory effects, as demonstrated convincingly in animal models. Several factors, including phosphate and vitamin D, can regulate the production of both FGF23 and Klotho and influence their functions. In various acquired and genetic human diseases, dysregulation of FGF23 and Klotho is associated with vascular and skeletal anomalies owing to altered phosphate turnover. In this Review, I summarize how the endocrine effects of bone-derived FGF23, in coordination with Klotho, can regulate systemic phosphate homeostasis, and how an inadequate balance of these molecules can lead to complications that are caused by abnormal mineral ion metabolism.

Figure 1

Serum phosphate lowering effects of FGF23. FGF23 (produced in the bone) can suppress NaPi-2a and NaPi-2c cotransporters, which results in increased renal excretion of phosphate. Similarly, FGF23 can suppress renal expression of 1-α hydroxylase, which leads to reduced production of calcitriol and decreased intestinal phosphate absorption, and subsequent reduced serum levels of phosphate.

Figure 2

Gross features, survival and serum FGF23 levels in Kl-knockout mice. Compared with WT mice, Kl^−/− mice are smaller in size (a), have markedly elevated serum levels of FGF23 (b) and have a shorter lifespan (around 15–20 weeks) (c). The serum level of FGF23 was measured by enzyme-linked immunosorbent assay using a commercial kit that detects the intact form of FGF23. *P <0.001 versus WT; data presented as mean ± SEM. Abbreviations: Kl^−/−, Kl-knockout; WT, wild type.

Figure 3

Renal expression of NaPi-2a and serum levels of phosphate in Kl-knockout mice. Compared with WT mice, Kl^−/− mice exhibit increased renal expression of NaPi-2a (a and b) and hyperphosphatemia (c). Note that hyperphosphatemia is observed in Kl^−/− mice by 3 weeks of age and their serum phosphate level remains high for their entire lifespan. *P <0.05 versus WT; data presented as mean ± SEM. Abbreviations: Kl^−/−, Kl-knockout; WT, wild type.

Figure 4

The endocrine effects of vitamin D on phosphate metabolism. Calcitriol increases urinary excretion of phosphate by inducing the expression of both FGF23 (in bone) and Klotho (in kidney), which results in decreased serum phosphate levels. Calcitriol can also facilitate increased intestinal absorption of phosphate, which increases serum phosphate levels.