Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Intact fibroblast growth factor 23 (iFGF23) is a phosphate regulating hormone secreted by bone. In chronic kidney disease (CKD), increased Fgf23 transcription is associated with cardiovascular mortality, disturbed iron metabolism and anemia. Fgf23 transcription is physiologically coupled to FGF23 cleavage by Furin resulting in secretion of iFGF23, carboxy terminal (Cter) and amino terminal (Nter) FGF23 peptides. The well-established function of iFGF23 is to maintain normal phosphate homeostasis by targeting the kidney but there is emerging evidence supporting extra-renal FGF23 targets which might be the result of increased Cter- and Nter-FGF23 signaling. Novel approaches to reduce FGF23-associated adverse outcomes in CKD are desperately needed but current therapies are suboptimal due to lack of understanding of the role of FGF23 peptides. In preliminary data we show that in addition to iFGF23, FGF23 peptides are secreted by bone and extraosseous sources, including erythroid cells, in CKD. We also show that these peptides display novel physiological functions. Cter-FGF23 peptides suppress the secretion of the hepatic iron regulatory hormone, hepcidin, leading to increased circulating iron. Nter-FGF23 peptides are not released in the circulation when FGF23 is expressed in bone, but in iron deficient animals and patients and mice with CKD, FGF23 production by erythroid cells contribute to increased circulating Nter-FGF23 levels. When elevated, Nter-FGF23 reduces the secretion of erythropoietin, inhibits erythropoiesis and induces left ventricular hypertrophy (LVH). These observations support important new roles of FGF23 peptides, and a functional role for the coupled regulation of Fgf23 transcription and iFGF23 cleavage. In Aim 1, we will establish the physiological and pathological role of Cter-FGF23 peptides in iron metabolism. Using multiple genetic mouse models, we will delete and overexpress Fgf23 and Cter-Fgf23 in bone, to test whether Cter-FGF23 peptides generated from increased FGF23 cleavage, protect mice against overt hypoferremia by uniquely limiting hepcidin secretion in models of high (inflammation and iron overload) or low (iron deficiency) endogenous hepcidin and compare these effects to exogenous hepcidin administration. We will further test the therapeutic potential of genetic and pharmacologic Cter-FGF23 supplementation in two mouse models of CKD and assess the onset and development of iron deficiency anemia. In Aim 2, we will use the genetic overexpression and pharmacologic administration of FGF23 and Nter-FGF23 in osteocytes and erythroid cells, in vivo and in vitro, to investigate the direct role of iFGF23, Nter-FGF23 and FGFR signaling in the inhibition of erythropoiesis, and their indirect role by regulating erythropoietin (EPO) production in kidney and liver. We will further investigate whether erythroid-produced Nter-FGF23 peptides contribute to LVH in mice with CKD and test the direct hypertrophic effects of Nter-FGF23 in cardiomyocytes cultures. This project will contribute to new insights into the molecular functions of FGF23 and support our ultimate goal of developing novel therapeutic approaches to improve adverse outcomes associated with excess FGF23.
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