Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men

Abstract

Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH) vitamin D metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH) vitamin D, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH) vitamin D are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH) D levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71 erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH) vitamin D levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism.

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort

“…A direct relationship between EPO and FGF23 has been shown as concentration of FGF23 increases after injection of recombinant human (rh) EPO in mice/rats as well as in humans. (16,17,38,39) In a murine model with chronically elevated EPO and normal renal function, similar results have been noted with positive association between EPO and serum levels of FGF23. (39) Furthermore, when injecting mice with FGF23, a decreased renal EPO mRNA has been noted, suggesting a negative feedback loop between EPO and FGF23.…”

“…We showed a positive correlation between EPO and iFGF23 as well as EPO and parameters of inflammation. A direct relationship between EPO and FGF23 has been shown as concentration of FGF23 increases after injection of recombinant human (rh) EPO in mice/rats as well as in humans . In a murine model with chronically elevated EPO and normal renal function, similar results have been noted with positive association between EPO and serum levels of FGF23 .…”

“…Several groups have recently suggested that EPO is a link between FGF23, hypoxia, and inflammation. (16,17,38) We showed a positive correlation between EPO and iFGF23 as well as EPO and parameters of inflammation. A direct relationship between EPO and FGF23 has been shown as concentration of FGF23 increases after injection of recombinant human (rh) EPO in mice/rats as well as in humans.…”

“…Several groups have recently proposed that EPO stimulates the production of fibroblast growth factor 23 (FGF23) . FGF23 is produced by osteocytes/blasts and is a known effector of bone mineralization.…”

“…Several groups have recently proposed that EPO stimulates the production of fibroblast growth factor 23 (FGF23). (16)(17)(18) FGF23 is produced by osteocytes/blasts and is a known effector of bone mineralization. It has been reported that serum FGF23 levels increase with chronic kidney disease with an evident increase as estimated glomerular filtration rate (eGFR) falls under 58 mL/min.…”