FGF23 from erythroblasts promotes hematopoietic progenitor mobilization.

Abstract Fibroblast growth factor-23 (FGF23) hormone is produced by bone-embedded osteocytes and regulates phosphate homeostasis in kidneys. We found that granulocyte colony-stimulating factor (G-CSF) administration in mice induced a rapid and tremendous increase in FGF23 mRNA in bone marrow (BM) cells. This increase mainly originated from CD45-Ter119+CD71+ erythroblasts. FGF23 protein in BM extracellular fluid was markedly increased during G-CSF-induced hematopoietic progenitor cell (HPC) mobilization but remained stable in the blood with no change in the phosphate level. Consistent with the BM hypoxia induced by G-CSF, low oxygen concentration induced FGF23 release from human erythroblast HUDEP-2 cells in vitro. The mobilization efficiency by G-CSF was drastically decreased in both FGF23-/- and chimeric mice with FGF23 deficiency only in hematopoietic cells but increased in osteocyte-specific FGF23-/- mice. This suggests that erythroblast-derived, but not bone-derived, FGF23 is required to release HPCs from BM to circulation. Mechanistically, FGF23 did not influence CXCL12 binding to CXCR4 on progenitors but interfered with their transwell migration toward CXCL12, which was canceled by FGF receptor inhibitors. These results suggest that BM erythroblasts facilitate G-CSF-induced HPC mobilization via FGF23 production as an intrinsic suppressor of chemoattraction.