Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism

Abstract

Derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification indicating that healthy people without these abnormalities maintain serum phosphate within certain ranges. These results indicate that there must be a regulatory mechanism of serum phosphate level. Fibroblast growth factor 23 (FGF23) was identified as the last member of FGF family. FGF23 is produced by bone and reduces serum phosphate level by suppressing phosphate reabsorption in proximal tubules and intestinal phosphate absorption through lowering 1,25-dihydroxyvitamin D level. It has been shown that excess and deficient actions of FGF23 result in hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. It may become possible to treat patients with abnormal phosphate metabolism by pharmacologically modifying the activity of FGF23.

Figure 1

Structure FGF23 protein. FGF23 is produced as a peptide with 251 amino acids. There is a signal peptide with 24 amino acids, and the secreted FGF23 protein consists of 227 amino acids. A part of FGF23 protein is proteolytically cleaved between ¹⁷⁹Arg and ¹⁸⁰Ser into inactive fragments by enzymes that recognize ¹⁷⁶R-¹⁷⁷X-¹⁷⁸X-¹⁷⁹R motif just before the processing site. FGF homology region is present in the N-terminal portion of this processing site of FGF23.

Figure 2

Actions of FGF23. FGF23 is produced by bone. FGF23 suppresses the expression of type 2a and 2c sodium-phosphate cotransporters (NaPi) in the brush border membrane of proximal tubules which mediate physiological phosphate reabsorption. In addition, FGF23 reduces serum 1,25(OH)₂D level by suppressing the expression of 25-hydroxyvitamin D [25(OH)D]-1α-hydroxylase and also enhancing the expression of 25(OH)D-24-hydroxylase. This 1α-hydroxylase mediates the production of 1,25(OH)₂D from 25(OH)D, and 24-hydroxylase converts 1,25(OH)₂D into more hydrophilic metabolites with less activity. Because 1,25(OH)₂D enhances intestinal phosphate absorption, FGF23 reduces serum phosphate level by its suppressive effects on renal phosphate reabsorption and intestinal phosphate absorption. Conversely, 1,25(OH)₂D increases FGF23 level. High phosphate diet also increases circulatory FGF23. However, it remains to be clarified how changes in dietary phosphate modulate FGF23 level.

Figure 3

Heterotrimer complex of Klotho, FGF23, and FGFR1c. Klotho, FGF23, and FGFR1c make a heterotrimer complex in order to transmit the signal of FGF23 to target organs. Therefore, Klotho seems to be necessary for FGF23 signaling. N: N-terminus of FGF23 protein; C: C-terminus of FGF23 protein.