Role of Hyperphosphatemia and 1,25-Dihydroxyvitamin D in Vascular Calcification and Mortality in Fibroblastic Growth Factor 23 Null Mice

Abstract

Fibroblastic growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1α-hydroxylase activity. Ablation of FGF23 results in elevated serum phosphate, calcium, and 1,25-dihydroxyvitamin D3 [1,25(OH)₂D] 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)₂D 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)₂D 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)₂D 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.