Multiple myeloma is a fatal plasma cell malignancy that is reliant on the bone marrow microenvironment. The bone marrow is comprised of numerous cells of mesenchymal and hemopoietic origin. Of these, macrophages have been implicated to play a role in myeloma disease progression, angiogenesis, and drug resistance; however, the role of macrophages in myeloma disease establishment remains unknown. In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169+ bone marrow-resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was attributed in part to decreased levels of macrophage-derived insulin-like growth factor 1. Moreover, a single dose of clodronate-liposome led to a significant reduction in myeloma tumor burden in KaLwRij mice with established disease. Collectively, these findings support a role for CD169-expressing bone marrow-resident macrophages in myeloma disease establishment and progression and demonstrate the potential of targeting macrophages as a therapy for myeloma patients.

中文翻译：

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氯膦酸盐脂质体介导的巨噬细胞耗竭消除体内多发性骨髓瘤肿瘤的建立。

多发性骨髓瘤是致命的浆细胞恶性肿瘤，依赖于骨髓微环境。骨髓由间充质和造血来源的许多细胞组成。其中，巨噬细胞被认为在骨髓瘤疾病的进展，血管生成和耐药性中起作用。然而，巨噬细胞在骨髓瘤疾病建立中的作用仍然未知。在这项研究中，在成熟的骨髓瘤C57BL / KaLwRijHsd鼠模型中评估了氯膦酸盐脂质体治疗的抗骨髓瘤功效，该作用可全局和暂时消耗巨噬细胞。我们的研究首次表明，氯膦酸盐脂质体预处理可消除体内骨髓瘤的发展。氯膦酸盐脂质体给药导致CD169 +骨髓驻留巨噬细胞耗竭。流式细胞仪分析显示，氯膦酸盐-脂质体预处理会损害骨髓瘤浆细胞接种后24小时骨髓瘤浆细胞的归巢和滞留。这部分归因于巨噬细胞源性胰岛素样生长因子1水平的降低。此外，单剂量的氯膦酸盐脂质体可显着降低患有已确诊疾病的KaLwRij小鼠的骨髓瘤肿瘤负荷。总的来说，这些发现支持表达CD169的骨髓驻留巨噬细胞在骨髓瘤疾病的建立和发展中的作用，并证明了靶向巨噬细胞作为骨髓瘤患者治疗的潜力。这部分归因于巨噬细胞源性胰岛素样生长因子1水平的降低。此外，单剂量的氯膦酸盐脂质体可显着降低患有已确诊疾病的KaLwRij小鼠的骨髓瘤肿瘤负荷。总的来说，这些发现支持表达CD169的骨髓驻留巨噬细胞在骨髓瘤疾病的建立和发展中的作用，并证明了靶向巨噬细胞作为骨髓瘤患者治疗的潜力。这部分归因于巨噬细胞源性胰岛素样生长因子1水平的降低。此外，单剂量的氯膦酸盐脂质体可显着降低患有已确诊疾病的KaLwRij小鼠的骨髓瘤肿瘤负荷。总的来说，这些发现支持表达CD169的骨髓驻留巨噬细胞在骨髓瘤疾病的建立和发展中的作用，并证明了靶向巨噬细胞作为骨髓瘤患者治疗的潜力。