Immuno-Skeletal Effects of Erythropoietin in Multiple Myeloma Mice - a Friend and Foe

Clinical introduction of recombinant human erythropoietin (Epo) has been a breakthrough in treating patients suffering from anemia associated with chronic kidney failure. We have previously reported that Epo treatment in multiple myeloma (MM) patients and mouse models was associated with improved immunological functions. We have recently found that Epo treatment or overexpression, stimulates bone resorption in mice (Hiram-Bab et al., 2015). Here we address Epo action on the immune and skeletal systems in the 5T33 MM mouse model.

Epo administration to MM mice attenuated disease progression as demonstrated by a significant decrease in MM pathological κ light chain, expression of IL-6 and RORγt (a Th17 hallmark). Interferon-γ transcript levels (activator cytokine of macrophages) and number of macrophages (F4/80⁺CD11b⁺) in the bone marrow (BM) were increased 1.7 and 1.4-fold, respectively in the Epo- versus vehicle-treated MM mice (p<0.05). In vitro, activation of purified BM-derived macrophages with Epo, led to a 33% increase (p=0.01) in phagocytosis of 5T33 MM cells.

High-resolution µCT analysis of the distal femurs revealed Epo-associated bone loss in both healthy and MM mice. B cells are a significant source of RANKL. Epo led to an increase (1.8-fold, p=0.0003) in membrane bound RANKL on B cells (B220⁺CD19⁺) isolated from BM. These cells expressed Epo receptors, suggesting that they are direct targets of Epo.

Taken together, these findings portray Epo as a double-edged sword, which stimulates immune response while accelerating bone resorption in MM. The current study highlights administration of targeted bone protective treatment alongside Epo in MM patients, to attenuate the anemia and MM progression, while preventing bone damage.

Supported by the MMRF and by the FP7 European commission grant; 282551 EpoCan.