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Abstract: TH-PO656

Paracrine FGF23 Signaling Suppresses Erythropoiesis in Iron Deficiency Anemia

Session Information

  • Anemia and Iron Metabolism
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Authors

  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Von Drasek, John Charles, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Iron deficiency anemia (IDA) stimulates fibroblast growth factor 23 (FGF23) production in osteocytes and erythroid cells, leading to excess circulating FGF23 derived fragments but only slightly elevated intact (iFGF23). Recent studies have suggested that rising iFGF23 in IDA negatively regulates erythropoiesis. However, the contribution of osteocytic and/or erythroid iFGF23 production to anemia remains to be determined.

Methods

We generated conditional Fgf23 knockout mice by deleting Fgf23 under the control of dentin matrix protein 1 (Dmp1) in osteocytes (Fgf23Dmp1-cKO) or hemoglobin Beta (HbB) in erythroid cells (Fgf23HbB-cKO). Next, we induced IDA in mutant and wild-type (WT) mice, by feeding animals a control (Ctr) or a low-iron diet (ID) from 3 to 6 weeks of age. In all mice, we analyzed serum biochemical parameters of iron metabolism, hematological parameters and bone marrow erythroid differentiation by flow cytometry and PCR. In parallel, we investigated the effects of FGF23 signaling in erythroid cell cultures, in presence of recombinant FGF23 and FGF receptors inhibitors.

Results

Compared to WT-Ctr mice, WT-ID mice developed IDA, marked by decreased serum iron, Hb content, increased erythroid progenitors, and a reduction in erythroblasts and reticulocytes number (p<0.05). WT-ID mice also showed a mild but significant increase in serum iFGF23 levels. Deletion of Fgf23 in osteocytes completely rescued iFGF23 levels in Fgf23Dmp1-cKO-ID mice. In sharp contrast, deletion of Fgf23 in erythroid cells only minimally decreased circulating iFGF23 levels. Intriguingly, suppression of Fgf23 in erythroid cells corrected the reductions in Hb in ID mice, whereas suppression of Fgf23 in bone did not. In addition, Fgf23HbB-cKO-ID mice showed a ~30% increase in erythroblasts and reticulocytes number compared to WT-ID mice. In line with these findings, erythroid progenitors treated with escalating doses of iFGF23 dose dependently blocked erythroid differentiation at precursor stage and reduced reticulocyte number. These effects were fully suppressed by co-treatment with FGFR1 inhibitor.

Conclusion

In aggregate, our results show that erythroid-produced iFGF23, but not circulating iFGF23, is a negative regulator of erythropoiesis and contributes to anemia via FGFR1 activation in erythroid precursors.

Funding

  • NIDDK Support