Abstract
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
Highlights
Erythropoiesis is an essential process that is finely regulated
This reviewtheir will importance focus on these pathwaysstudies and describe their focus on these pathways describe in preclinical and clinical importance in preclinical studies and clinical applications, because they are the target of applications, because they are the target of new therapeutic agents which have proved to new therapeutic agents which have proved to be highly effective in improving anemia asbe highly effective in improving anemia associated with myelodysplastic syndromes (MDS), β-thalassemia and chronic sociateddisease
It was observed that the in vitro treatment with a miR-21 inhibitor increased the expression of SMAD7 and erythroid colony formation in samples obtained from MDS patients [18]. These results indicated that the reduced activity of SMAD7, caused by the increased levels of miR-21, was the cause of the overactivation of SMAD2/3 and of the consequent ineffective erythropoiesis in MDS, and that this pathway could be a potential therapeutic target to correct anemia in MDS patients (Figure 2)
Summary
Erythropoiesis is an essential process that is finely regulated. All stages are controlled by several molecules and several signal transduction pathways are implicated. Some data hint at a relevant role for phospholipase C and PI3K in erythropoiesis regulation.and. This reviewtheir will importance focus on these pathwaysstudies and describe their focus on these pathways describe in preclinical and clinical importance in preclinical studies and clinical applications, because they are the target of applications, because they are the target of new therapeutic agents which have proved to new therapeutic agents which have proved to be highly effective in improving anemia asbe highly effective in improving anemia associated with MDS, β-thalassemia and chronic sociateddisease.
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