Erythroid-produced intact FGF23 is a paracrine inhibitor of erythropoiesis.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and chronic kidney disease (CKD), FGF23 is also produced by erythroid cells. Recent studies have suggested that rising circulating FGF23 is negatively associated with erythropoiesis in IDA and CKD. However, the distinct contributions of bone- and erythroid-produced FGF23 to anemia in IDA remain unclear. Using the conditional deletion of Fgf23 in osteocytes (Fgf23Dmp1-cKO) and in erythroid cells (Fgf23HbB-cKO) in mice fed a control or an iron-deficient (ID) diet, we first determined that in iron deficiency, osteocytes and erythroid cells are distinct sources of circulating intact FGF23 (iFGF23) and FGF23-cleaved peptides, respectively. We further showed that erythroid-specific deletion of Fgf23 corrected anemia in ID mice, whereas overexpression induced anemia in control mice, unlike osteocyte-specific deletion or overexpression of Fgf23. Importantly, erythroid-specific deletion of Furin (FurinHbB-cKO), the enzyme responsible for FGF23 cleavage, led to the increased production of iFGF23 from erythroid cells and aggravated ID-induced anemia. Furthermore, iFGF23 dose-dependently blocked the differentiation of erythroid progenitors in culture, triggering mitochondrial dysfunction that led to impaired erythropoiesis. These effects were fully suppressed by cotreatment with an FGFR1 inhibitor. Finally, erythroid-specific deletion of Fgf23 in an animal model of progressive CKD prevented the development of anemia of CKD. Collectively, our results show that erythroid-expressed FGF23 is a negative regulator of erythropoiesis that contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors.