Acute FGF23 neutralization alters phosphate handling and bone marrow molecular responses in sickle cell disease mice

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, but its role in erythropoiesis and the bone marrow environment in sickle cell disease (SCD) remains unclear. We examined acute FGF23 neutralization in 7-month-old female Townes SCD mice. Mice received a single subcutaneous dose of FGF23-neutralizing antibody (10 mg/kg) or control IgG, and samples were collected 12 h later. Urinary phosphate excretion, serum hepcidin and erythropoietin (EPO), bone marrow erythroid populations, cell-cycle distribution, apoptosis, erythroid colony formation, and bone marrow gene expression were assessed. SCD mice exhibited increased urinary phosphate excretion, reduced serum hepcidin, and markedly elevated serum EPO compared with controls. FGF23 neutralization significantly reduced urinary phosphate excretion and further increased serum EPO, whereas the modest increase in hepcidin was not significant. Bone marrow Ki67 expression was increased in SCD mice and showed a non-significant reduction after FGF23 blockade. Notably, Pit1 (Slc20a1) expression was markedly increased in SCD bone marrow and was significantly reduced by FGF23 neutralization. Expression of EpoR, Fgf23, αKlotho, Fgfr1, Fgfr2, Fgfr3c, Fgfr4, Bax, and Bcl2 was not significantly altered. Acute FGF23 blockade also did not significantly affect erythroid colony-forming capacity, cell-cycle distribution, differentiation, or apoptosis. These findings demonstrate that acute FGF23 neutralization rapidly alters phosphate handling and selected bone marrow molecular responses in SCD, particularly Pit1 expression, without measurable changes in erythroid progenitor colony-forming capacity. The FGF23-phosphate axis may therefore contribute to regulation of the bone marrow environment in SCD.