Erythropoietin treatment in murine multiple myeloma: Immune gain and bone loss

Naamit Deshet-Unger, Sahar Hiram-Bab, Yasmin Haim-Ohana, Moshe Mittelman, Yankel Gabet, Drorit Neumann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 RORÎ 3Ï., transcripts in bone marrow (BM). IFN-Î 3 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.

Original languageEnglish
Article number30998
JournalScientific Reports
Volume6
DOIs
StatePublished - 2 Aug 2016

Funding

FundersFunder number
FP7-Health European commission EpoCan
Sackler Faculty of Medicine
Schauder Memorial Endowment Fund
Multiple Myeloma Research Foundation
Minneapolis Medical Research Foundation
Seventh Framework Programme282551
Israel Cancer Association
Israel Science Foundation1822/12
Tel Aviv University
Sackler Faculty of Medicine, Tel-Aviv University

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