文章：

外泌体通过靶向破骨细胞和成骨细胞在多发性骨髓瘤骨病和肿瘤发展中发挥作用

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

原文发布日期：2018-11-08

DOI: 10.1038/s41408-018-0139-7

类型: Article

开放获取: 是

英文摘要：

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

摘要翻译： 

多发性骨髓瘤（MM）的进展主要依赖于骨髓（BM）微环境，其中通过包括细胞外囊泡在内的不同因子进行通信。这种相互作用不仅导致耐药性，还会引发骨质溶解。因此，靶向囊泡分泌可能同时改善药物反应和骨病。在本文中，我们使用5TGM1小鼠模型研究了MM外泌体对骨质溶解不同方面的影响。我们发现5TGM1 sEVs（即“外泌体”）不仅增强破骨细胞活性，还在体外阻断成骨细胞分化和功能。从机制上，我们证实DKK-1的转移导致成骨细胞中Runx2、Osterix和胶原蛋白1A1的减少。在体内实验中，我们发现5TGM1外泌体能够以与MM细胞自身相似的模式诱导骨质溶解。使用鞘磷脂酶抑制剂GW4869阻断外泌体分泌，不仅增加了皮质骨体积，还使骨髓瘤细胞对硼替佐米敏感，当GW4869与硼替佐米联合使用时产生强烈的抗肿瘤反应。总之，我们的研究结果揭示了外泌体在骨髓微环境中的重要作用，并为抗骨髓瘤治疗提出了新的治疗靶点。

原文链接：

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts