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Abstract: SA-OR034

C-FGF23 Peptide Protects Against Severe Hypoferremia During Acute Inflammation

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Courbon, Guillaume, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Chonira, Vikas, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Capella, Maralee, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, 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

Inflammatory stimuli induce functional iron deficiency, by increasing the expression of the hepatic iron regulatory
peptide, hepcidin. Acute inflammation stimulates fibroblast growth factor 23 (FGF23)
production in bone and leads to a dramatic increase in both Fgf23 transcription and FGF23 cleavage and
paradoxically leads to excess in C-terminal FGF23 peptides (cFGF23), but not intact hormone (iFGF23). This
questions the physiological need for increased Fgf23 transcription in this context and we hypothesized that cFGF23
peptides might actively participate in the regulation of iron metabolism by regulating hepcidin expression.

Methods

We induced acute inflammation in WT, FGF23-null and FGF23-DMP1cKO mice using a single dose of 250ng/g of interleukin 1 beta (IL1b) and we analyzed the effects on iron homeostasis. We next used recombinant cFGF23 peptides as bait in cultured osteoblasts to immunoprecipitate (IP) and to identify binding partners by mass spectrometry (MS). We also verified binding between FGF23 peptides and putative partners using bio-layer interferometry (BLI). Finally, we administered cFGF23 to verify its impact on iron metabolism.

Results

As expected IL1b administration to WT mice led to low serum iron and transferrin saturation (TSAT) due to high hepcidin levels, and increased bone Fgf23 expression and secretion of cFGF23 peptides (p<0.05). FGF23-DMP1cKO mice had 90% lower FGF23 levels (p<0.05), but exhibited further reductions in serum iron and TSAT compared to IL1b-treated WT, due to higher serum hepcidin and liver Hamp (encoding hepcidin) mRNA, suggesting that cFGF23 reduces Hepcidin production. Using IP/MS, we next identified binding of cFGF23 peptides to members of the bone morphogenic protein (BMP) family, BMP2 and BMP9, established inducers of hepcidin, and we confirmed binding of BMP2 and BMP9 to cFGF23 by BLI. In WT mice, co-administration of cFGF23 and BMP2 or BMP9 prevented the increase in Hamp mRNA and circulating hepcidin levels resulting in normal serum iron levels and TSAT. In addition, injection of cFGF23 increased serum iron levels and TSAT in WT and FGF23-null mice.

Conclusion

This is the first study to provide a new direct role for bone-produced cFGF23 peptides to antagonize the
inflammation-induced BMP signaling in the liver and inhibit the secretion of the iron regulatory peptide, hepcidin.

Funding

  • NIDDK Support