骨髓瘤骨病（MMBD）是多发性骨髓瘤（MM）的常见合并症。MMBD与成骨细胞形成受抑制等因素相关，而成骨细胞是由骨髓间充质基质细胞（MSCs）分化而来。申请人近期研究发现MSCs可以通过内吞途径摄取MM外泌体，促进MSCs活力增强以及诱导多条通路激活。预实验证实MMBD骨髓中和MM细胞分泌的外泌体中都含有高水平miR-138，这些外泌体可以被MSCs摄取并且抑制MSCs的成骨分化。因此我们设想MM细胞可以通过外泌体传递miR-138至MSCs而后作用于成骨相关的靶基因抑制MSCs的成骨分化，导致成骨进程受阻，加速了骨溶解和MMBD的产生。我们将通过体外实验以及利用SCID-beige小鼠模型，使用多种分子生物学方法以及micro-CT等手段，系统研究骨髓瘤外泌体通过miR-138与MSCs相互作用对成骨分化的影响，以期发现新的骨髓瘤骨病治疗靶点，为研制新的MMBD的治疗药物奠定基础。

Myeloma bone disease (MMBD) is a common complication of multiple myeloma (MM). MMBD is closely associated with inhibition of osteoblast formation. Osteoblasts can be differentiated from bone marrow mesenchymal stromal cells (MSCs). Our recent study found that MM exosomes can be taken up by MSCs through endocytosis to increase viability of MSCs and activate multiple pathways. Our preliminary data showed that exosomes isolated from MM cell lines and the BM of MMBD patients contain high level of miR-138, and these exosomes can be taken up by MSCs and inhibit MSCs differentiation to osteoblasts. Thus,we hypothesized that MM cell-derived exosomes deliver miR-138 to MSCs and therefore inhibit osteogenic differentiation of MSCs by targeting osteogenesis-related genes, leading to obstruction of osteogenesis, acceleration of osteolysis and induction of MMBD. We will use in vitro experiments and SCID-beige mouse model, as well as multiple molecular biology methods and micro-CT, to systematically study the effect of myeloma exosomes on osteogenic differentiation through exosomes-mediated miR-138 delivery, in order to favor the discovery of new therapeutic targets and provide the foundation of developing new therapeutic drugs for MMBD.