calcitriol and Phosphorus-Metabolism-Disorders

Serum phosphate is maintained within a certain range by intestinal phosphate absorption, renal phosphate handling, and dynamic equilibrium with the intracellular phosphate or phosphate in bone. Of these, renal phosphate handling is believed to be the main determinant of the serum phosphate level at least in a chronic state. Most of the phosphate filtered from the glomeruli is reabsorbed in proximal tubules through type 2a and 2c sodium-phosphate co-transporters. Therefore, chronic hypophosphatemia and hyperphosphatemia are usually caused by changes in renal phosphate handling. Several humoral factors, including parathyroid hormone and insulin-like growth factor-I, have been known to affect proximal tubular phosphate reabsorption. In addition, fibroblast growth factor 23 (FGF23) was shown to inhibit phosphate reabsorption by suppressing the expression of type 2a and 2c sodium-phosphate co-transporters. FGF23 also reduces the circulatory 1,25-dihydroxyvitamin D [1,25 (OH)2D] level. FGF23 is produced by bone, especially by osteocytes, and works in the kidney by binding to the Klotho-FGF receptor complex. It has been shown that excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia with impaired proximal tubular phosphate reabsorption and a rather low 1,25 (OH)2D level. In contrast, deficient actions of FGF23 result in familial hyperphosphatemic tumoral calcinosis with enhanced proximal tubular phosphate reabsorption and high 1,25 (OH)2D. These results indicate that FGF23 is a hormone regulating phosphate and vitamin D metabolism. In addition, several hypophosphatemic and hyperphosphatemic diseases can be classified as endocrine diseases caused by the aberrant actions of FGF23. It is possible that some drugs that modulate the action of FGF23 can be novel therapeutic measures for abnormal phosphate metabolism in the future.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Hypophosphatemia; Kidney; Osteomalacia; Phosphates; Phosphorus Metabolism Disorders; Rickets; Vitamin D

Fibroblastic growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1alpha-hydroxylase activity. Ablation of FGF23 results in elevated serum phosphate, calcium, and 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D] levels; vascular calcifications; and early death. For determination of the independent roles of hyperphosphatemia and excess vitamin D activity on the observed phenotypic abnormalities, FGF23 null mice were fed a phosphate- or vitamin D-deficient diet. The phosphate-deficient diet corrected the hyperphosphatemia, prevented vascular calcifications, and rescued the lethal phenotype in FGF23 null mice, despite persistent elevations of serum 1,25(OH)(2)D and calcium levels. This suggests that hyperphosphatemia, rather than excessive vitamin D activity, is the major stimulus for vascular calcifications and contributes to the increased mortality in the FGF23-null mouse model. In contrast, the vitamin D-deficient diet failed to correct either the hyperphosphatemia or the vascular calcifications in FGF23 null mice, indicating that FGF23 independently regulates renal phosphate excretion and that elevations in 1,25(OH)(2)D and calcium are not sufficient to induce vascular calcifications in the absence of hyperphosphatemia. The vitamin D-deficient diet also improved survival in FGF23 null mice in association with normalization of 1,25(OH)(2)D and calcium levels and despite persistent hyperphosphatemia and vascular calcifications, indicating that excessive vitamin D activity can also have adverse effects in the presence of hyperphosphatemia and absence of FGF23. Understanding the independent and context-dependent interactions between hyperphosphatemia and excessive vitamin D activity, as well as vascular calcifications and mortality in FGF23 null mice, may ultimately provide important insights into the management of clinical disorders of hyperphosphatemia and excess vitamin D activity.

Topics: Animals; Calcinosis; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Mice; Mice, Knockout; Phosphorus Metabolism Disorders; Vascular Diseases; Vitamin D