FGF23 and Phosphate Wasting Disorders

Abstract

A decade ago, only two hormones, parathyroid hormone and 1,25(OH)2D, were widely recognized to directly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 (FGF23) in 2000 (1), our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteoblasts in the skeleton (2-3), it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimentalto humans. In this review, we will discuss the pathophysiology of FGF23 and hyper-FGF23 related renal phosphate wasting disorders (4 IntroductionAccording to pathogenesis, ricketsis classified into calicopenic rickets, phosphopenicrickets, and a miscellaneous group associated with direct inhibitors of mineralization ( 5). In general, most instances of nutritional rickets are calicopenic, whereas heritable causes are usually phosphopenic. In this review we focus on hypophosphatemic rickets or osteomalacia. The causes of hypophosphatemia are various, of whichthe most prominent one is decreased reabsorption of phosphate in the proximal tubule.Although renal tubular disease can result in excessive renal phosphate wasting, in most hypophosphatemic disordersno abnormalities are found in the proximal tubule (6-7). It is speculated that an unknown factor is responsible for this phenomenon. The discovery of fibroblast growth factor 23 (FGF23), a member of the Phosphate homeostasisPhosphate comprises about 1% of total body weight. About 85% of total body phosphate resides in the bone, 14% in the cells, and only 1% in the serum and extracellular fluids. Maintenance of serum phosphate within its normal range allows for optimal mineralization of bone without deposition in vascular and other soft tissues. Serum phosphate concentration is determined Xianglan Huang et al. www.boneresearch.org | Bone Research 121by the balance among intestinal absorption of phosphate from the diet, its storage in bone, and its excretion in the urine. The proximal tubule is responsible for the reabsorption of phosphate filtered at the glomerulus and is the primary regulator of phosphate balance in the body. Transportation in the proximal tubule is driven primarily by sodium-potassium ATPase, which is located in the baso-lateral membrane of the cell (8-11). Under normal conditions, about 85% of the filtered phosphate is reabsorbed via the sodium-phosphate co-transporter (NaPi2a and NaPi2c) in the proximal tubule (9, 11). Parathyroid hormone (PTH) is one of the most potent horm...

High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss

“…To identify proteins that contributed to phytate-mediated impairment of renal tubular Ca 2+ and phosphate reabsorption, we analyzed the mRNA levels of key renal genes associated with Ca 2+ and phosphate homeostasis, including those associated with Ca 2+ , phosphate channels, and regulatory proteins (Mulay and Anders, 2017; Huang et al, 2013). We found that the renal expression of key genes associated with renal phosphate wasting, including Ca 2+ sensing receptor (CaSR), inositol 1,4,5-trisphosphate receptor 1 (ITPR1), αKlotho, sodium/phosphate cotransporters (NaPi-2a and NaPi-2c), sodium-hydrogen antiporter 3 regulator 1 (NHERF1), and phosphate-regulating neutral endopeptidase X-linked was markedly decreased in phytate-fed rats ( figure supplement 7A ).…”

“…We found that the renal expression of key genes associated with renal phosphate wasting, including Ca 2+ sensing receptor (CaSR), inositol 1,4,5-trisphosphate receptor 1 (ITPR1), αKlotho, sodium/phosphate cotransporters (NaPi-2a and NaPi-2c), sodium-hydrogen antiporter 3 regulator 1 (NHERF1), and phosphate-regulating neutral endopeptidase X-linked was markedly decreased in phytate-fed rats ( figure supplement 7A ). Each of these genes is associated with the development of nephrocalcinosis and renal phosphate wasting (Shavit et al, 2015; Huang et al, 2013; Karim et al, 2008; Monico and Milliner, 2011).…”

Phosphate wasting disorders in adults

“…Definition ARHR is another rare hereditary renal phosphate wasting disorder characterized by hypophosphatemia, rickets, and/or osteomalacia and slow growth [32,52].…”

Phosphate Homeostasis, Inflammation and the Regulation of FGF-23

“…The excessive increase of plasma FGF23 concentrations, compromized 1,25(OH) 2 D 3 formation and renal phosphate wasting in patients carrying loss of function mutations of PHEX [20,22]) interferes with bone mineralization leading to several clinical disorders including limb deformity, short stature, arthritis, enthesopathy, hearing impairment, optic atrophy and nephrocalcinosis [21][22][23][24]. Loss of function mutations of DMP-1 lead to rickets/ osteomalacia later during childhood or in adulthood [23].…”

“…Loss of function mutations of DMP-1 lead to rickets/ osteomalacia later during childhood or in adulthood [23].…”