Effects of erythropoietin on fibroblast growth factor 23 in mice and humans

Hanudel, Mark R.; Eisenga, Michele F.; Rappaport, Maxime; Chua, Kristine J.; Qiao, Bo; Jung, Grace; Gabayan, Victoria; Gales, Barbara; Ramos, Georgina Varela; Jong, Maarten A. de; Zanden, Jelmer J. van; Borst, Martin H. de; Bakker, Stephan J. L.; Nemeth, Elizabeta; Salusky, Isidro B.; Gaillard, Carlo A. J. M.; Ganz, Tomas

doi:10.1093/ndt/gfy189

Cited by 80 publications

(105 citation statements)

References 49 publications

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“…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.…”

Section: Discussionsupporting

confidence: 73%

“…(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. (17) Effort was made adjusting for levels of FGF23 when assessing EPO's effect on fracture risk.…”

Section: Discussionsupporting

confidence: 73%

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

Kristjánsdóttir

Lewerin

Lerner

et al. 2019

Journal of Bone and Mineral Research

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Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean AE SD EPO was 11.5 AE 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = −0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray-verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35-1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08-1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00-2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 73%

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

Kristjánsdóttir

Lewerin

Lerner

et al. 2019

Journal of Bone and Mineral Research

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“…WT mice given acute rhEPO treatment after 6 h or after 3–4 days of consecutive injections resulted in elevated total and intact FGF23 and bone marrow Fgf23 mRNA expression ( 64 ). To understand the effects of chronically elevated EPO, reports using the transgenic Tg6 mouse model of EPO overexpression showed that these mice have basal elevations in total and intact FGF23 ( 65 , 67 ). Chronic overexpression of EPO can lead to iron deficiency, so to determine whether the iron deficiency was causing the elevated FGF23, mice were given iron dextran.…”

Section: Fgf23 Production and Cleavage In Osteocytesmentioning

confidence: 99%

Osteocytic FGF23 and Its Kidney Function

Agoro

Noonan

et al. 2020

Front. Endocrinol.

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Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH) 2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.

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“…Regulators of FGF23 production in bone include 1,25(OH) 2 D 3 , PTH, inflammation, the iron status, erythropoietin, intracellular posttranslational regulators (GalNAc‐T and FAM20c; ) as well as intracellular signaling pathways (eg, AMP‐dependent signaling or phosphoinositide 3‐kinase (PI3K) signaling). FGF23‐expressing UMR106 osteoblast‐like cells express both, endothelin A (ETA) and endothelin B receptors (ETB)…”

Section: Introductionmentioning

confidence: 99%

Endothelin receptor B controls the production of fibroblast growth factor 23

et al. 2020

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Endothelin-1 (ET-1) is a member of the endothelin family of peptide hormones first discovered as endothelium-derived mediators regulating vascular tone. ET-1 also regulates the proliferation and differentiation of bone cells that synthesize fibroblast growth factor 23 (FGF23). FGF23 is a hormone controlling renal phosphate and vitamin D metabolism. Here, we studied the role of ET-1 and endothelin receptor B (ETB) for FGF23 production. Fgf23 gene expression was studied in IDG-SW3 bone cells by quantitative RT-PCR. ETB-expressing (etb +/+ ) and rescued ETBdeficient mice (etb −/− ) were studied in metabolic cages. Their serum FGF23, PTH, and 1,25(OH) 2 D 3 concentrations were determined by ELISA, serum and urinary phosphate and Ca 2+ by photometric methods. ET-1 and ETB agonist sarafotoxin 6c suppressed Fgf23 mRNA in IDG-SW3 cells. Serum C-terminal and intact FGF23 as well as bone Fgf23 mRNA levels were significantly higher in etb −/− mice than in etb +/+ mice. Renal phosphate excretion was significantly higher in etb −/− mice despite lower phosphate levels. In addition, etb −/− animals exhibited calciuria and a significantly higher serum 1,25(OH) 2 D 3 concentration compared to etb +/+ mice. In conclusion, ETB-dependent ET-1 signaling is a potent suppressor of FGF23 formation. This effect is likely to be of clinical relevance given the use of endothelin receptor antagonists in various diseases. K E Y W O R D SET-1, klotho, phosphate, vitamin D

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Effects of erythropoietin on fibroblast growth factor 23 in mice and humans

Abstract: EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

Cited by 80 publications

References 49 publications

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

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

Osteocytic FGF23 and Its Kidney Function

Endothelin receptor B controls the production of fibroblast growth factor 23

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