Non-canonical function of erythropoietin and downstream effects of erythropoietin-mediated signaling beyond its role in erythropoiesis.

INTRODUCTION

Recombinant human erythropoietin (rHuEPO) and its derivatives, which are called erythropoiesis-stimulating agents (ESAs), have long been indispensable molecules to treat patients with anemia due to their high effectiveness in stimulating erythropoiesis. Previous studies have indicated the additional effects of EPO besides erythropoiesis such as suppressing inflammation and apoptosis.

AREAS COVERED: This review summarizes the physiology of EPO and its receptors, describes the pathways other than erythropoiesis activated by recombinant human EPO and their derivatives, and discusses the potential benefits of non-erythropoietic EPO receptor agonists (ERAs). Literature search was conducted using Google Scholar and PubMed databases.

EXPERT OPINION: Previous studies indicate the protective effects of ESAs in various disease models, some of which are independent of their erythropoietic feature. However, ESAs contain safety concerns, especially when administered in high dose to fully bring out their favorable effects. ERAs that only activate the non-erythropoietic reactions by EPO seem to be equally beneficial in improving outcome without serious adverse effects, which raises expectations for their further investigation in large clinical trials. So far, non-erythropoietic ERAs are not clinically available yet, and clinicians should understand the risks associated with ESAs upon their usage.