FGF-23 Is a Negative Regulator of Prenatal and Postnatal Erythropoiesis

Coe, Lindsay M.; Vadakke‐Madathil, Sangeetha; Casu, Carla; Lanske, Beate; Rivella, Stefano; Sitara, Despina

doi:10.1074/jbc.m113.527150

Cited by 125 publications

(132 citation statements)

References 46 publications

(59 reference statements)

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“…Alternative hypothesis have included phosphorusinduced accumulation of polyamine toxins [19] , increased production of diphosphoglycerate and adenosine triphosphate, leading to rightward shift in the oxygen-hemoglobin dissociation curve and subsequent downregulation of erythropoietin receptors [15] and increased levels of fibroblast growth factor (FGF-23) [18,19] . With regard to the latter, recent investigations on murine models have shown that genetic inactivation of either FGF-23 or klotho, an essential cofactor in FGF-23 signaling pathways, entails a substantial increase in erythropoietic activity in all hematopoietic tissues, a greater expression of erythropoietin mRNA in bone marrow, liver and kidney, and an increase in circulating erythropoietin levels [35,36] . With respect to a possible relationship between serum calcium and anemia, it has been practically unnoticed until now.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Anemia and Serum Concentrations of Calcium and Phosphorus in Advanced Non-Dialysis-Dependent Chronic Kidney Disease

Boronat¹,

Santana²,

Bosch³

et al. 2016

Nephron

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Background/Aims: Different biochemical abnormalities of metabolic bone disease have been associated with anemia of chronic kidney disease (CKD), mainly in hemodialysis patients. However, all of these abnormalities are closely inter-related and their individual effect on the development of anemia is uncertain. This study was aimed to assess the relationship between anemia and a set of metabolic bone disease biomarkers in a cohort of adult patients with advanced non-dialysis-dependent CKD. Methods: The sample consisted of 382 patients submitted to a Nephrology Unit for evaluation of advanced CKD in a tertiary hospital from Gran Canaria during 3 years. Associations between anemia and serum levels of calcium (albumin-corrected), phosphorus, PTH, 25-hydroxivitamin D (25(OH)D₃) and alkaline phosphatase were analyzed by using logistic regression models with adjustment for other demographic, clinical and biochemical covariates potentially related to anemia and to bone mineral metabolism. Results: Serum levels of calcium and 25(OH)D₃ (negatively) and phosphorus (positively) were significantly associated with anemia in an unadjusted logistic regression model. In a fully adjusted multivariable model, the OR for anemia was 0.29 (95% CI 0.16-0.49; p < 0.0001) for every 1 mg/dl increase in serum calcium and 2.19 (95% CI 1.55-3.15; p < 0.001) for every 1 mg/dl increase in serum phosphorus. Female sex and lower serum albumin levels were also independently associated with anemia. The inclusion of albumin in the adjusted model displaced the significance of 25(OH)D₃. Conclusions: Circulating levels of calcium and phosphorus are strongly linked to anemia in patients with advanced non-dialysis CKD.

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Section: Discussionmentioning

confidence: 99%

Relationship between Anemia and Serum Concentrations of Calcium and Phosphorus in Advanced Non-Dialysis-Dependent Chronic Kidney Disease

Boronat¹,

Santana²,

Bosch³

et al. 2016

Nephron

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“…FGF23 signaling is involved in immune regulation through impairment of macrophage and neutrophil function [27]. Preclinical data suggest a novel role for elevated FGF23 in hematopoiesis through impairment of erythropoiesis in bone marrow cells [28]. Deletion of FGF23 in wild-type mice resulted in increased erythropoiesis in bone marrow independent of vitamin D, and exogenous FGF23 administration resulted in a rapid decrease in erythropoiesis [28].…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical data suggest a novel role for elevated FGF23 in hematopoiesis through impairment of erythropoiesis in bone marrow cells [28]. Deletion of FGF23 in wild-type mice resulted in increased erythropoiesis in bone marrow independent of vitamin D, and exogenous FGF23 administration resulted in a rapid decrease in erythropoiesis [28]. FGF23 levels in the latter studies were parallel to levels detected in murine models with CKD, supporting the hypothesis that elevation of FGF23 observed in CKD may contribute to the development of anemia [29].…”

Section: Discussionmentioning

confidence: 99%

Ferric Citrate Decreases Fibroblast Growth Factor 23 and Improves Erythropoietin Responsiveness in Hemodialysis Patients

et al. 2018

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Background: Serum phosphate and vitamin D receptor activator regulate fibroblast growth factor 23 (FGF23), and iron may modulate FGF23 metabolism. The aim of the present study was to elucidate the effects of ferric citrate hydrate and lanthanum carbohydrate on serum FGF23 levels in hemodialysis patients. Methods: This prospective, open-label, multicenter study enrolled 60 patients on hemodialysis treated with lanthanum carbonate. Patients were randomly assigned to 2 groups: those switching from lanthanum carbonate to ferric citrate hydrate (ferric citrate group, n = 30) or those continuing lanthanum carbonate (control group, n = 30). Patients were monitored for 24 weeks. Endpoints included changes in FGF23, phosphate, and the dose of erythropoiesis stimulating agent (ESA), erythropoietin responsiveness index (ERI), and adverse events. Results: FGF-23 levels were significantly lower in the ferric citrate group compared with the levels in the control group (change from baseline –6,160 vs. –1,118 pg/mL; p = 0.026). There were no significant changes in serum calcium, phosphate, and intact parathyroid hormone levels in either group. The ferric citrate group had significantly increased serum iron, ferritin, and transferrin saturation. Hemoglobin levels were significantly elevated, and the dose of ESA was significantly decreased in the ferric citrate group but not in the control group. ERI and the dose of intravenous saccharated ferric oxide were significantly lower in the ferric citrate group compared with those of the control group (p = 0.015 and p = 0.002). Conclusion: In patients on hemodialysis, 24-week treatment with ferric citrate hydrate resulted in significant reduction in FGF23 and ERI independently of serum phosphate level.

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“…Intriguingly, 1,25(OH) 2 D 3 levels in bone marrow are a magnitude higher in comparison to their levels in plasma [22]. Animal experiments have revealed that FGF23 deficiency leads to hyperphosphatemia paralleled with increased levels of vitamin D and enhanced prenatal and postnatal erythropoiesis [23]. However, enhanced erythropoiesis in those mice was shown to be independent of increased 1,25(OH) 2 D 3 levels [23].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D-Rich Diet in Mice Modulates Erythrocyte Survival

Lang

Jilani

Bissinger

et al. 2015

Kidney Blood Press Res

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Background/Aims: Epidemiological evidence suggests that vitamin D deficiency is associated with anemia. The potent metabolite 1,25(OH)₂ vitamin D₃ [1,25(OH)₂D₃] activates various signaling cascades regulating a myriad of cellular functions including suicidal cell death or apoptosis. Suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Stimulation of eryptosis may limit lifespan of circulating erythrocytes and thus cause anemia. In the present study, we explored the effect of a high vitamin D diet (10,000 I.U. vitamin D for 14 days) in mice on eryptosis. Methods: Plasma concentrations of erythropoietin were estimated using an immunoassay kit, blood count using an electronic hematology particle counter, relative reticulocyte numbers using Retic-COUNT® reagent, PS exposure at the cell surface from annexin V binding, cell volume from forward scatter, and cytosolic Ca²⁺ ([Ca²⁺]_i) from Fluo3-fluorescence in FACS analysis. Results: Vitamin D treatment decreased mean corpuscular volume, reticulocyte count, and plasma erythropoietin levels. Vitamin D treatment slightly but significantly decreased forward scatter but did not significantly modify spontaneous PS exposure and [Ca²⁺]_i of freshly drawn erythrocytes. Vitamin D treatment augmented the stimulation of PS exposure and cell shrinkage following exposure to hyperosmotic shock (addition of 550 mM sucrose) or energy depletion (glucose removal) without significantly modifying [Ca²⁺]_i. Conclusions: The present observations point to a subtle effect of exogenous vitamin D supplementation on erythrocyte survival.

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FGF-23 Is a Negative Regulator of Prenatal and Postnatal Erythropoiesis

Cited by 125 publications

References 46 publications

Relationship between Anemia and Serum Concentrations of Calcium and Phosphorus in Advanced Non-Dialysis-Dependent Chronic Kidney Disease

Relationship between Anemia and Serum Concentrations of Calcium and Phosphorus in Advanced Non-Dialysis-Dependent Chronic Kidney Disease

Ferric Citrate Decreases Fibroblast Growth Factor 23 and Improves Erythropoietin Responsiveness in Hemodialysis Patients

Vitamin D-Rich Diet in Mice Modulates Erythrocyte Survival

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