FGF23 Regulation of Phosphorus Homeostasis Is Dependent on PTH

Abstract

Fibroblast growth factor-23 (FGF23) is a key regulator of phosphorus homeostasis (1). FGF23 is a member of the FGF19 subfamily of fibroblast growth factors. The FGF23 gene is located on human chromosome 12p13 and mouse chromosome 6 and is composed of three coding exons with an open reading frame of 125 residues. FGF23 is most highly expressed in bone but also found in thymus, brain, heart, and other tissues. In bone, FGF23 mRNA is found in osteoblasts, osteocytes, bone-lining cells, and osteoprogenitor cells. FGF23 is secreted primarily by osteoblasts and osteocytes in response to increased serum phosphorus or 1,25-dihydroxyvitamin D. Circulating FGF23 binds to the canonical FGF receptor 1c coupled to the single transmembrane protein Klotho, a coreceptor required for FGF23 signaling, to form the specific receptor for FGF23 function (2). FGF23 targets the parathyroid gland to decrease PTH secretion and the kidney to increase urinary phosphorus excretion and to suppress synthesis of 1,25-dihydroxyvitamin D by decreasing renal tubular 1 -hydroxylase expression. These changes result in increased urinary loss of phosphorus as well as decreased proximal renal tubular production of 1,25dihydroxyvitamin D, both of which lead to a return to normal serum phosphorus levels (Fig. 1). In the kidney, circulating FGF23 reduces the expression of proximal renal tubular brush border membrane sodium-phosphate cotransporters NaPi2a and NaPi2c, which reduces the ability of the kidney to reabsorb phosphorus from proximal renal tubular glomerular filtrate, thereby causing increased urinary loss of phosphorus (3). FGF23 also reduces the activity of proximal renal tubular 1 -hydroxylase, the enzyme required for production of 1,25-dihydroxyvitamin D and increases the activity of 24-hydroxylase, the proximal renal tubular enzyme that metabolizes 1,25-dihydroxyvitamin D. Decreased serum 1,25-dihydroxyvitamin D leads to decreased intestinal calcium and phosphorus absorption, and low serum calcium and low serum 1,25-dihydroxyvitamin D both lead to increased production of PTH. The main physiological short-term role of circulating FGF23 appears to be to stimulate renal tubular phosphorus excretion when excessive phosphorus intake leads to hyperphosphatemia, whereas its main long-term role appears to be to limit intestinal absorption of phosphorus. Progressive increases in serum FGF23 play a major role in mineral metabolism abnormalities that develop in disorders characterized by hyperphosphatemia. Serum FGF23 levels increase in early-stage chronic kidney disease (CKD) and are associated with progressive hyperphosphatemia and hypocalcemia in late-stage CKD, secondary hyperparathyroidism, and low 1,25-dihydroxyvitamin D levels. Serum FGF23 levels increase beginning as early as stage 2 CKD because of decreased renal tubular clearance of phosphorus and result in increased fractional phosphorus excretion, reduced serum phosphorus levels, and reduced renal 1 -hydroxylase activity, which lead to normalization of serum phosphorus and reduced serum 1,25-dihydroxyvitamin D levels. Increased serum phosphorus levels in later-stage CKD, despite increased serum FGF23 levels and low serum 1,25dihydroxyvitamin D levels, lead to persistent stimulation of PTH secretion. As CKD progresses, serum FGF23 continues to increase, whereas responsiveness to FGF23 decreases as the number of intact nephrons declines. Decreased intact nephrons are associated with reduced expression of the FGF23 coreceptor Klotho. In end-stage