Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism

Abstract

There are a number of hypophosphatemic disorders due to renal phosphate wasting that cannot be explained by elevated levels of parathyroid hormone. The circulating factors responsible for the phosphaturia have been designated as phosphatonins. Studies of patients with tumor-induced osteomalacia and other genetic diseases of phosphate metabolism have resulted in the identification of a number of hormones that regulate phosphate homeostasis, including matrix extracellular phosphoglycoprotein (MEPE), secreted frizzled-related protein 4 (sFRP-4), dentin matrix protein 1 (DMP1), fibroblast growth factor 7 (FGF7), fibroblast growth factor 23 (FGF23), and Klotho. Our understanding of the actions of these hypophosphatemic peptides has been enhanced by studies in mice either overexpressing or not expressing these hormones. This review focuses on FGF23 since its regulation is disordered in diseases that affect children, such as X-linked hypophosphatemia, autosomal dominant and recessive hypophosphatemic rickets as well as chronic kidney disease. Recent studies have shown that FGF23 is unique among the FGFs in its requirement for Klotho for receptor activation. Here, we also discuss new potentially clinically important data pointing to the receptor(s) that mediate the binding and action of FGF23 and Klotho.

Fig. 1

Fibroblast growth factor 23 (FGF23)–kidney–gastrointestinal tract–parathyroid axis. This figure demonstrates the complex interaction between the various hormones that play a role in phosphate homeostasis. FGF23 is primarily produced in the bone, which decreases the expression of an electrogenic phosphate transporter (sodium-dependent phosphate transporter 2a, NaPi-2a) and an electro-neutral phosphate transporter (NaPi-2c) on the apical surface of the proximal tubule, causing phosphaturia. FGF23 also decreases the serum levels of 1,25(OH)₂ vitamin D_3. Decreased 1,25(OH)₂ vitamin D₃ levels in turn decreases the gastrointestinal absorption of phosphorus. 1,25(OH)₂ Vitamin D₃ stimulates FGF23 production, which in turn decreases 1,25(OH)₂ vitamin D₃. FGF23 directly or indirectly decreases NaPi-2b expression in the small intestine. Serum parathyroid hormone (PTH) stimulates the synthesis of 1,25(OH)₂ vitamin D₃, which in turn decreases PTH levels as a negative feedback mechanism. PTH also decreases NaPi-2a and NaPi-2c expression. FGF23 decreases PTH secretion. The solid lines indicate positive regulation, and the dotted lines indicate negative regulation

Fig. 2

FGF23–Klotho binding to the FGF receptor and schematic representation of the actions of FGF23 in the proximal tubular cell. This figure shows the interaction between the FGF receptor (FGFR), FGF23, Klotho, and heparin on the surface of the cell. FGF23 binds to the FGFR–Klotho complex with heparin stabilizing this complex. Activation of FGFR results in the activation of intracellular signaling pathways, which in turn decreases the expression of NaPi-2a, NaPi-2c, and 1α-hydroxylase. This results in decreased phosphate absorption from the proximal tubule and decreased synthesis of 1,25(OH)₂ vitamin D₃