Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation

Abstract

Inflammation leads to functional iron deficiency, by increasing the expression of the hepatic iron regulatory peptide, hepcidin. Inflammation also stimulates fibroblast growth factor 23 (FGF23) production by increasing both Fgf23 transcription and FGF23 cleavage, which paradoxically leads to excess in C-terminal FGF23 peptides (Cter-FGF23), rather than intact hormone (iFGF23). We determined that the major source of Cter-FGF23 are the osteocytes and investigated whether Cter-FGF23 peptides play a direct role in the regulation of hepcidin and iron metabolism in response to acute inflammation. Mice harboring an osteocyte-specific deletion of Fgf23 showed a ~90% reduction in Cter-FGF23 levels during acute inflammation. Reduction in Cter-FGF23 led to a further decrease in circulating iron in inflamed mice due to excessive hepcidin production. We observed similar results in mice showing impaired FGF23 cleavage due to osteocyte-specific deletion of Furin. We next showed that Cter-FGF23 peptides bind members of the bone morphogenic protein (BMP) family, BMP2 and BMP9, which are established inducers of hepcidin. Co-administration of Cter-FGF23 and BMP2 or BMP9 prevented the increase in Hamp mRNA and circulating hepcidin levels induced by BMP2/9, resulting in normal serum iron levels. Finally, injection of Cter-FGF23 in inflamed Fgf23KO mice and genetic overexpression of Cter-Fgf23 in WT mice also resulted in lower hepcidin and higher circulating iron levels. In conclusion, during inflammation, bone is the major source of Cter-FGF23 secretion and independently of iFGF23, Cter-FGF23 reduces BMP-induced hepcidin secretion in the liver.

Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism

“…Intact FGF23 is mainly secreted from osteocytes and osteoblasts in bone [40–43]. In our recent study, we also report that IL-1β directly enhances Fgf23 promoter activity [12 ▪▪ ], and stimulates Fgf23 transcription in bone in response to both acute and chronic inflammation. Among several tissues expressing increased Fgf23 mRNA, bone and especially cortical bone was the major contributor in terms of RNA quantities and fold increase.…”

“…Among several tissues expressing increased Fgf23 mRNA, bone and especially cortical bone was the major contributor in terms of RNA quantities and fold increase. The conditional deletion of Fgf23 in late osteoblasts and osteocytes corrected the excess of both intact FGF23 and Cter-FGF23 peptides in inflammation in vivo , and secretion of FGF23 in vitro [12 ▪▪ ]. In such conditions, over 90% of FGF23 is cleaved [6], by Furin, since deletion of Furin in late osteoblasts and osteocytes in mice led to increased stabilization of intact FGF23.…”

“…Thus, the reason for increased FGF23-derived peptides concomitant with relatively normal iFGF23 levels remains unclear, if these peptides are devoid of a biologically relevant function. Recently, we have found that cleaved C-terminal FGF23 peptides (Cter-FGF23) secreted from osteoblasts and osteocytes in response to functional iron deficiency minimize hypoferremia in a hepcidin-dependent mechanism [12 ▪▪ ]. In mice, reduction in cleaved Cter-FGF23 peptides aggravated hypoferremia while exogenous administration and/or transgenic overexpression of these peptides reduced inflammation-induced functional iron deficiency.…”

“…Interestingly, a kinetics study of FGF23 regulations in a model of functional iron deficiency induced by i.p. injection of IL-1β revealed a dramatic increase in FGF23 stimulation 1 h postinjection, and generation of cleaved Cter-FGF23 peptides in 2 h, reaching its peak before 6 h following administration of the cytokine [12 ▪▪ ]. Despite such a strong and rapid response to stimuli related to inflammation and iron, FGF23 excess also persists in chronic inflammation suggesting sustained elevations of this hormone in a context without perturbed phosphate metabolism [12 ▪▪ ].…”

Editorial: Crosstalk between bone and other cells

“…FGF-23 also downregulates the expression and activity of 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in the renal proximal tubular cells, thereby reducing the action of 1,25-dihydroxyvitamin D 3 ( Perwad et al, 2007 ). During acute inflammation, osteocytes release certain mediators including C-terminal FGF-23 peptides to modulate hepatic hepcidin production and serum iron ( Courbon et al, 2023 ). Moreover, osteocalcin or γ-carboxyglutamic acid-containing protein—as an osteoblast-derived endocrine factor—is capable of regulating pancreatic insulin production ( Lee et al, 2007 ), adiponectin release from adipocytes ( Lee et al, 2007 ) or testicular androgen biosynthesis ( Karsenty and Oury, 2014 ).…”