PTH ablation ameliorates the anomalies of Fgf23-deficient mice by suppressing the elevated vitamin D and calcium levels

Fibroblast growth factor 23 (FGF23) is a key regulator of mineral ion homeostasis. Genetic ablation of Fgf23 in mice leads to severe biochemical disorders including elevated serum 1,25-dihydroxyvitamin D [1,25(OH) ₂D], hypercalcemia, hyperphosphatemia, and marked decreased PTH levels. Because PTH stimulates 1,25(OH) ₂D production and increases serum calcium levels, we hypothesized that ablation of PTH from the Fgf23 knockout (Fgf23 ^-/-) mice could suppress these affects, thus ameliorating the soft tissue and skeletal anomalies in these animals. In this study, we generated a genetic mouse model with dual ablation of the Fgf23/PTH genes. The data show that deletion of PTH does suppress the markedly higher serum 1,25(OH) ₂D and calcium levels observed in Fgf23 ^-/- mice and results in much larger, heavier, and more active double-knockout mice with improved soft tissue and skeletal phenotypes. On the contrary, when we infused PTH (1-34) peptide into Fgf23 ^-/- mice using osmotic minipumps, serum 1,25(OH) ₂D and calcium levels were increased even further, leading to marked reduction in trabecular bone. These results indicate that PTH is able to modulate the anomalies of Fgf23 ^-/- mice by controlling serum 1,25(OH) ₂D and calcium levels.