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Editorials
response to inflammation,15 nor did C-FGF23 pretreatment reduce hepatic levels of phosphorylated STAT3, the major intracellular mediator of hepcidin induction by inflamma- tory cytokines.1 However, interestingly, in livers of LPS- treated mice, C-FGF23 pretreatment lowered levels of mRNA encoding BMP6, a key ligand for a major signaling pathway promoting hepcidin transcription.16 Additionally, in LPS-treated mice, C-FGF23 pretreatment raised splenic mRNA levels of erythroferrone, a negative regulator of hepcidin expression that is synthesized by erythroblasts.17
Another area to be clarified is whether the observed effects of C-FGF23 pretreatment on gene expression, as well as on iron storage, in liver and spleen are mediated through the ability of C-FGF23 to act as a competitive inhibitor of FGFR expressed by these organs. Indeed, although the co-receptor Klotho is expressed primarily in the kidney, parathyroid gland, and brain, recent work sug- gests that under conditions of FGF23 elevation the FGF23 hormone can participate in FGFR-dependent signaling mechanisms in tissues lacking Klotho.10 Another possibili- ty is that C-FGF23 may mediate FGFR-independent bio- logical actions that either directly or indirectly impact iron regulatory pathways. Because the gene expression responses found to be modulated by C-FGF23 were meas- ured in organs of heterogenous cellular composition, such as liver and spleen, it will also be valuable to clarify the participating cell types.
It is also worth considering the fact that the FGF23 C- terminal peptide introduced into mice in this study corre- sponds to the human peptide sequence; the murine and humans forms of FGF23 share 64% amino acid homology across this portion of the protein. To exclude the possibil- ity that some observed responses to human C-FGF23 in mice reflect more general immunomodulatory effects that occur due to the introduction of a foreign peptide, it will be valuable to clarify if pretreatment with murine C- FGF23 produces similar effects on iron homeostasis in LPS-treated mice.
In terms of clinical relevance, the ability of C-FGF23 to attenuate the hypoferremia, hepatic and splenic iron sequestration, and renal suppression of Epo mRNA observed 4 hours after LPS injection raises the intriguing possibility that C-FGF23-based approaches may have rel- evance for treatment of anemia of inflammation. Future studies in which the ability of C-FGF23 to modulate these physiological parameters is assessed longitudinally after LPS injection will be informative. Additionally, it will be of great interest to determine if long-term admin- istration of C-FGF23 produces beneficial effects on iron
metabolism and erythropoiesis in animal models in which anemia of inflammation has already been achieved through chronic exposure to infectious or non- infectious stimuli.18 It will also be of interest to character- ize the effects of chronic C-FGF23 administration on phosphate and calcium homeostasis in animal models of the anemia of inflammation.
Disclosures
No conflicts of interest to disclose.
References
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