Physiological Actions of Fibroblast Growth Factor-23

Abstract

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. At physiological concentrations of the hormone, the endocrine actions of FGF23 in the kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the presence of the co-receptor αKlotho on target cells. It is well established that excessive concentrations of intact FGF23 in the blood lead to phosphate wasting in patients with normal kidney function. Based on the importance of diseases associated with gain of FGF23 function such as phosphate-wasting diseases and chronic kidney disease, a large body of literature has focused on the pathophysiological consequences of FGF23 excess. Less emphasis has been put on the role of FGF23 in normal physiology. Nevertheless, during recent years, lessons we have learned from loss-of-function models have shown that besides the paramount physiological roles of FGF23 in the control of 1α-hydroxylase expression and of apical membrane expression of sodium-phosphate co-transporters in proximal renal tubules, FGF23 also is an important stimulator of calcium and sodium reabsorption in distal renal tubules. In addition, there is an emerging role of FGF23 as an auto-/paracrine regulator of alkaline phosphatase expression and mineralization in bone. In contrast to the renal actions of FGF23, the FGF23-mediated suppression of alkaline phosphatase in bone is αKlotho-independent. Moreover, FGF23 may be a physiological suppressor of differentiation of hematopoietic stem cells into the erythroid lineage in the bone microenvironment. At present, there is little evidence for a physiological role of FGF23 in organs other than kidney and bone. The purpose of this mini-review is to highlight the current knowledge about the complex physiological functions of FGF23.

Keywords: 1α-hydroxylase; Klotho; alkaline phosphatase; bone mineralization; fibroblast growth factor-23; phosphate metabolism; vitamin D.

Figure 1

Physiological functions of fibroblast growth factor-23 (FGF23). FGF23 is mainly produced in bone cells, osteoblasts, and osteocytes. One of the main target organs of the hormone FGF23 is the kidney. In the kidney, FGF23 acts on proximal and distal convoluted renal tubules. Binding of blood-borne FGF23 to FGF receptor-1c (FGFR1c) requires the presence of the co-receptor αKlotho. In renal proximal tubules (PT), FGF23 inhibits phosphate (Pi) re-uptake and expression of 1α-hydroxylase (CYP27B1), the rate-limiting enzyme for vitamin D hormone (1α,25(OH)₂D₃) production. The FGF23-mediated suppression of 1α-hydroxylase transcription involves extracellular signal-regulated kinase-1 and 2 (ERK1/2) activation. However, the exact signaling pathway downstream of ERK1/2 is unknown. The inhibition of phosphate reabsorption in proximal renal tubules by FGF23 is mediated through activation of ERK1/2 and serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na⁺/H⁺ exchange regulatory cofactor (NHERF)-1. NHERF-1 phosphorylation triggers internalization and degradation of the sodium-phosphate cotransporter NaPi-2a, so that less NaPi-2a is available in the apical membrane for phosphate uptake from urine. In distal convoluted tubules (DCT), FGF23 increases reabsorption of calcium and sodium by increasing the apical membrane abundance of the epithelial calcium channel transient receptor potential vanilloid-5 and of the sodium-chloride cotransporter NCC through a signaling cascade involving ERK1/2, SGK1, and with-no-lysine kinase-4 (WNK4). FGF23 locally produced by osteocytes is an auto-/paracrine inhibitor of bone mineralization by down-regulating tissue non-specific alkaline phosphatase (TNAP) transcription in a αKlotho-independent fashion via FGFR1- or FGFR3-mediated activation of ERK1/2. The signaling pathway downstream of ERK1/2, leading to suppression of TNAP transcription, is not known. TNAP is essential for normal mineralization of bone by cleaving the mineralization inhibitor pyrophosphate (PPi).