The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research

Abstract

We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…P i affects erythrocyte function directly [ 289 , 290 ] and indirectly via FGF23 [ 328 ]. Hypophosphatemia reduces the concentration of 2,3-BPG in erythrocytes, since P i is required for the synthesis of ATP and thus for the glycolytic synthesis of the 2,3-BPG precursor, 1,3-bisphosphoglycerate [ 290 ].…”

Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia

“…On the other hand, EPO has been shown to augment the iFGF23 cleavage resulting in increased C-FGF23 levels while blocking the FGF23 pathway led to increased EPO levels in mice [35]. In light of the above, one should expect increased cleavage of iFGF23 and higher levels of C-FGF23.…”

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study

“…HIF may play a role in the association between FGF23 and anaemia. Mouse and human studies found that physiological response to iron deficiency may be regulating FGF23 through erythropoietin production and HIF activation 42 . Furthermore, erythropoietin‐FGF23 signalling pathway was discovered to play important role in erythroid cell development and bone mineralization 43 .…”