title: Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis.
abstract: BACKGROUND
  Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits.
  
  
  METHODS
  EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases.
  
  
  CONCLUSIONS
  While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a's effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs.
authors.affiliation: a 1 Maine Medical Center Research Institute, Molecular Medicine Division , Scarborough, ME, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Rainville
authors.affiliation: a 1 Maine Medical Center Research Institute, Molecular Medicine Division , Scarborough, ME, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Jachimowicz
authors.affiliation: a 1 Maine Medical Center Research Institute, Molecular Medicine Division , Scarborough, ME, USA.|b 2 Tufts University School of Medicine , Boston, MA, USA.|c 3 Maine Medical Center Research Institute, Center of Excellence in Stem & Progenitor Cell Biology and Regenerative Medicine , Scarborough, ME 04074, USA ; wojchd@mmc.org.|d 4 Tufts University School of Medicine , Boston, MA, USA.
authors.forename: Don M
authors.initials: DM
authors.lastname: Wojchowski
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D015195:Drug Design; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use; D006397:Hematinics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D017467:Receptors, Erythropoietin / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D006397:Hematinics; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin
keywords: Spi2a; anemia; erythroferrone; erythroid models; erythropoiesis; erythropoiesis-stimulating agents; erythropoietin; erythropoietin receptor; hypoxia inducible factors; janus kinase 2; prolyl hydroxylases; protein tyrosine phosphatases