Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss.
Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss.
复制标题
DOI：
10.1038/srep30998
复制
发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Neumann D
中科院分区：
文献类型：
--
作者：
Deshet-Unger N;Hiram-Bab S;Haim-Ohana Y;Mittelman M;Gabet Y;Neumann D
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，以溶骨性病变和单克隆免疫球蛋白为特征。贫血，伴随着疾病往往是治疗与重组人EPO。EPO的各种非红细胞生成作用使我们质疑其在5 T33 MM小鼠模型中对免疫系统和骨的联合作用。通过血清MM IgG 2b、脾脏CD 138表达细胞、骨髓（BM）中IL-6和RORγτ转录物的减少证明，给予MM小鼠EPO可减缓疾病进展。EPO处理的MM小鼠中，BM中的IFN-γ转录水平和巨噬细胞（F4/80+ CD 11b+）均增加约1.5倍。在体外，EPO刺激BM衍生的巨噬细胞对5 T33 MM细胞的吞噬作用（+30%）。相比之下，股骨远端的高分辨率microCT分析显示，健康和5 T33 MM小鼠中均存在EPO相关的骨丢失。EPO显著增加了健康小鼠破骨细胞生成核因子-κ B配体（RANKL）的表达，但在MM小鼠中没有，可能是由于对MM进展的拮抗作用。因此，在MM中，EPO可能作为一把双刃剑刺激免疫应答，同时加速骨吸收，可能通过直接作用于BM巨噬细胞。本研究支持一种谨慎的治疗MM患者贫血的方法，旨在维持EPO相关的抗MM作用，同时考虑骨损伤。
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.