Multiple myeloma-derived exosomes inhibit osteoblastic differentiation and improve IL-6 secretion of BMSCs from multiple myeloma
Multiple myeloma-derived exosomes inhibit osteoblastic differentiation and improve IL-6 secretion of BMSCs from multiple myeloma
复制标题
多发性骨髓瘤来源的外泌体抑制成骨细胞分化并改善多发性骨髓瘤 BMSC 的 IL-6 分泌
DOI：
10.1136/jim-2019-001010
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发表时间：
2020-01-01
影响因子：
2.6
通讯作者：
Fu, Rong
中科院分区：
文献类型：
--
作者：
Liu, Zhaoyun;Liu, Hui;Fu, Rong
骨髓基质细胞(BMSCs)通过细胞接触、分泌细胞因子、生长因子和细胞外小泡，在多发性骨髓瘤(MM)的发病机制中发挥重要作用。Exosome几乎由所有类型的细胞分泌，最近报道通过传递信使RNAs、lncRNAs和蛋白质来介导局部细胞间的串扰。研究表明，骨髓间充质干细胞来源的外切体可诱导多发性骨髓瘤细胞的增殖、迁移、存活和耐药。然而，MM细胞来源的外切体是否也在骨髓间充质干细胞的功能中发挥作用仍不清楚。本实验研究了MM细胞来源的外切体对MM患者BMSC分泌IL-6和成骨分化能力的影响，并检测了IL-6分泌相关调节蛋白APE1和NF-kB以及成骨细胞分化蛋白Runx2、Osterix和Ocn的表达。结果表明，MM细胞来源的外切体促进IL-6的分泌，抑制BMSCs的成骨分化和矿化。从机制上，我们证明了MM细胞来源的外切体导致骨髓间充质干细胞APE1和NF-kB的表达增加，而Runx2、Osterix和OCN的表达减少。综上所述，骨髓瘤细胞来源的外切体诱导骨髓间充质干细胞分泌IL-6，成骨分化不良。
Bone marrow stromal cells (BMSCs) play a critical role in multiple myeloma (MM) pathogenesis by cell contact, and secretion of cytokines, growth factors and extracellular vesicles. Exosomes are secreted by almost all cell types and are recently reported to mediate local cell-to-cell cross-talk by transferring messenger RNAs, LncRNAs, and proteins. Compelling studies have identified BMSC-derived exosomes induce proliferation, migration, survival, and drug resistance of MM cells. However, whether MM cell-derived exosome also plays a role in function in BMSC remains unclear. Here we investigated the effect of MM cell-derived exosomes on the interleukin (IL)-6 secretion and osteoblastic differentiation capability of BMSC from patients with MM. Furthermore we investigated the IL-6 secretion relative regulation protein APE1 and NF-kB and osteoblastic differentiation protein Runx2 (runt-related gene 2), Osterix and osteocalcin (OCN). Our results showed that MM cell-derived exosomes promoted IL-6 secretion and suppressed osteoblastic differentiation and mineralization of BMSCs. Mechanistically, we demonstrated that MM cell-derived exosomes lead to an increase in APE1 and NF-kB and a reduction in Runx2, Osterix and OCN in BMSCs. Taken together, MM cell-derived exosomes induce the secretion of IL-6 and poor osteoblastic differentiation of BMSCs.