FGF23 Is Not Required to Regulate Fetal Phosphorus Metabolism but Exerts Effects Within 12 Hours After Birth

Loss of fibroblast growth factor-23 (FGF23) causes hyperphosphatemia, extraskeletal calcifications, and early mortality; excess FGF23 causes hypophosphatemia with rickets or osteomalacia. However, FGF23 may not be important during fetal development. FGF23 deficiency (Fgf23 null) and FGF23 excess (Phex null) did not alter fetal phosphorus or skeletal parameters. In this study, we further tested our hypothesis that FGF23 is not essential for fetal phosphorus regulation but becomes important after birth. Although coreceptor Klotho null adults have extremely high FGF23 concentrations, intact FGF23 was normal in Klotho null fetuses, as were fetal phosphorus and skeletal parameters and placental and renal expression of FGF23 target genes. Pth/Fgf23 double mutants had the same elevation in serum phosphorus as Pth null fetuses, as compared with normal serum phosphorus in Fgf23 nulls. We examined the postnatal time courses of Fgf23 null, Klotho null, and Phex null mice. Fgf23 nulls and Klotho nulls were normal at birth, but developed hyperphosphatemia, increased renal expression of NaPi2a and NaPi2c, and reduced renal phosphorus excretion between 5 and 7 days after birth. Parathyroid hormone remained normal. In contrast, excess FGF23 exerted effects in Phex null males within 12 hours after birth, with the development of hypophosphatemia, reduced renal expression of NaPi2a and NaPi2c, and increased renal phosphorus excretion. In conclusion, although FGF23 is present in the fetal circulation at levels that may equal adult values, and there is robust expression of FGF23 target genes in placenta and fetal kidneys, FGF23 itself is not an important regulator of fetal phosphorous metabolism.