FGF23 is a relatively recently discovered (2001) key player in maintaining appropriate levels of serum phosphate. There are human genetic diseases that result in either decreased or increased plasma levels of FGF23. Using mouse models where the FGF23 gene was knocked out resulted in an impaired renal phosphate excretion as well as changes in the regulation of the renal 25(OH)D3-1α-hydroxylase that led to an overproduction of 1α,25(OH)2D3 resulting in hypercalcemia.

FGF23 is principally secreted by bone osteocytes/ osteoblasts but smaller amounts are present in the brain, muscle, heart, thymus, and spleen. FGF23 generates its biological responses through binding to its cognate plasma membrane spanning receptor (see Figure 1). FGF23 also requires the presence of both a protein cofactor known as klotho (1024 amino acids; 122 kDa) and the FGF23 receptor to create a functional trimeric complex. Both the C-termini of klotho and the phosphorylated FGF23 receptor span the plasma membrane as a hetero-dimer which generates an as yet unknown signal transduction second messenger(s).

Fig1. Schematic of binding of Fibroblast Growth Factor 23 (FGF23) to its receptor in a proximal kidney cell, resulting in the reduction of gene expression of two sodium and phosphate transporters and also the 25(OH)D3-1α-hydroxylase. The FGF23 receptor requires the presence of a protein cofactor known as klotho to generate its signal transduction signals. Generation of biological responses by FGF23 requires the interaction on the surface of the proximal (basal lateral) side of the kidney cell of FGF23 binding to a Klotho-FGF receptor dimeric complex creating formation of a trimeric complex. This trimeric complex then activates phosphorylation of the FGF receptor and activation of the intracellular signal activating the ERK kinase pathway. This then leads to the reduction of gene expression of the NaPi-2a and NaPi-2c electrogenic phosphate transporters and also the expression of the 25(OH)D3-1α-hydroxylase.

In the proximal renal tubule cells (Figure 1) the FGF23 receptor generated messengers result in two separate responses. One is an impairment of two classes of Na+-dependent phosphate transporters (NaPi-2a and NaPi-2c) which results in a reduction in renal tubular phosphate reabsorption. The second response works in the cell nucleus to reduce the expression of 25(OH)D3-1α-hydroxylase leading to a reduction in the production of 1α,25(OH)2D3 and lowering of 1α,25(OH)2D3 plasma levels.

A separate important action of FGF23 occurs in parathyroid secreting cells where FGF23 with its receptor and klotho and also 1α,25(OH)2D3 with its VDR separately work in the nucleus to reduce the production of PTH mRNA (see Figure 2).

Fig2. Regulation of PTH secretion via changes in stability of the PTH messenger RNA. The plasma membrane Ca2+ receptor of the PTH secreting cell senses changes in the serum Ca2+ level through a seven-transmembrane G protein linked to phospholipases that sends a second messenger to the cellular site of the regulation of the PTH mRNA concentration (see the two gold stars). Changes in the rate of secretion of PTH PTh secreting cells are mediated by changing the stability of the PTH mRNA. In the inset below the cell, there are two schematic diagrams of the PTH mRNA from 5′-UTR to 3′-UTR. The More stable mRNA schematic illustrates the circumstance of hypocalcemia, resulting in an increase in the stability of PTH mRNA and ultimately greater PTH secretion. The Less stable mRNA schematic illustrates the circumstance of hypercalcemia (with associated low serum phosphate) resulting in reduction of PTH mRNA stability and ultimately lower PTH secretion. Two key regulatory proteins (UNR and AUF1) bind to the 3′ untranslated region (3′UTR) of the PTH mRNA stabilizing PTH mRNA levels necessary to increase PTH secretion. In contrast, the K homology-type Splicing Regulatory Protein (KSRP) also binds to the PTH mRNA 3′-UTR, specifically to the ARE (Adenine- and uridine-Rich Elements) which is a conserved 26 nucleotide sequence that decreases PTH mRNA stability and as a consequence reduces PTH secretion. When KSRP is phosphorylated on serine-181 it cannot bind to the 3′-UTR ARE region (More stable mRNA) and there is no reduction of PTH mRNA stability and accordingly PTH secretion is increased. But when KSRP is not phosphorylated, it can bind (Less stable mRNA) to the PTH mRNA 3′-UTR ARE region, thus decreasing PTH mRNA stability and thereby reducing the secretion of PTH. Pin1 is a peptidyl- cis-trans isomerase that specifically binds to the unphosphorylated Ser/Thr-Pro protein motif of KSRP. This catalyzes the cis/trans isomerization of the KSRP proline peptide bonds, thus causing a conformational change in KSRP and increasing the biological activity of KSRP so that it can bind to the ARE nucleotide sequence of the PTH mRNA, which then results in a decrease in both the stability of the PTH mRNA and the secretion of PTH. The PTH secreting cell also has receptors for both 1α,25(OH)2D3 (produced by the kidney) and FGF-23 (produced by bone). Both hormones downregulate PTH gene transcription, thus lowering PTH production and secretion.

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مواضيع ذات صلة

Motor Functions of the Intestinal Tract

Control of Renal Magnesium Excretion and Extracellular Magnesium ion Concentration

Regulation of Renal Phosphate Excretion

Control of Calcium Excretion by the Kidneys

Summary of Major Factors That Regulate Potassium Secretion

Overview of Renal Potassium Excretion

Regulation of Internal Potassium Distribution

Production of Steroid Hormones—An Introduction

Profile of Bodily Cholesterol

Classes of Steroids

Modulation of the intestinal microbiome can alter in insulin sensitivity

Pathophysiology of obesity and diabetes