title: Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss.
abstract: Multiple myeloma (MM) is a plasma cell malignancy, characterized by osteolytic lesions and monoclonal immunoglobulins. The anemia, accompanying the disease is often treated with recombinant human EPO. Diverse non-erythropoietic effects of EPO have led us to question its combined action on the immune system and bone in the 5T33MM mouse model. EPO administration to MM mice attenuated disease progression as demonstrated by a decrease in serum MM IgG2b, splenic CD138 expressing cells, IL-6 and RORγτ transcripts in bone marrow (BM). IFN-γ transcript levels and macrophages (F4/80(+)CD11b(+)) in the BM both increased ~1.5 fold in the EPO-treated MM mice. In-vitro, EPO stimulated phagocytosis of 5T33MM cells (+30%) by BM-derived macrophages. In contrast, high-resolution microCT analysis of distal femurs revealed EPO-associated bone loss in both healthy and 5T33MM mice. EPO significantly increased expression of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in healthy mice, but not in MM mice, likely due to antagonizing effects on MM progression. Thus, in MM, EPO may act as a double-edged-sword stimulating immune response, while accelerating bone resorption, possibly via direct action on BM macrophages. This study supports a prudent approach of treating anemia in MM patients, aiming to maintain EPO-associated anti-MM effects, while considering bone damage.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Naamit
authors.initials: N
authors.lastname: Deshet-Unger
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.|Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Sahar
authors.initials: S
authors.lastname: Hiram-Bab
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Haim-Ohana
authors.affiliation: Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Mittelman
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Drorit
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications* / Q000276:immunology; D010587:Phagocytosis / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004921:Erythropoietin