基于外泌体环状RNA介导HDAC4/RANKL通路调控破骨细胞功能探讨温阳化瘀法干预骨髓瘤溶骨性病变的研究

约80%多发性骨髓瘤患者存在溶骨性病变，中药干预常能取得更好疗效。骨髓瘤细胞分泌的外泌体介导的破骨细胞活性异常是导致溶骨性病变的一个重要原因，外泌体中的有害物质即是中医“瘀”微观的体现，据《素问•至真要大论》的“寒者温之…结者散之”治则，提出假说：“温阳化瘀”法能干预“瘀”导致的破骨细胞线粒体功能及活性异常。.前期发现与骨髓瘤溶骨性病变正相关的外泌体特异性circRNA并进行生信分析找到了miR-6791-3p/HDAC4轴，临床及实验证明桂枝茯苓丸对骨髓瘤有效。拟提取骨髓瘤细胞株外泌体、建立骨髓瘤溶骨性病变小鼠等模型，使用自发性骨髓瘤小鼠模型，从组织、细胞、分子及基因水平，检测破骨细胞活性、HDAC4/RANKL信号通路、线粒体功能、microCT检测等方法，解析桂枝茯苓胶囊调控外泌体中特异性circRNA干预骨髓瘤溶骨性病变的机制，本研究将为温阳化瘀法治疗该病以获更好疗效提供科学依据。

80% of multiple myeloma(MM) patients suffer from osteolytic lesions which treated with Traditional Chinese medicine can get better effects. The abnormal activity of osteoclasts mediated by exosomes secreted by myeloma cells plays a critical role to induce osteolytic lesions. The harmful substances in exosomes could be recognized as the microscopic embodiment of "blood stasis" of traditional Chinese medicine. According to the therapeutic principles consist of "Cold requiring Warming…Stagnation requiring Dispersion"，which were put forward in the "Suwen zhizhenyaodalun", we hypothesize that "Warming Yang and Dissolving Stasis" could reverse abnormal activity and mitochondrial function of osteoclasts caused by "blood stasis"..Based on the previous research that the aberrant expression of specific circRNA in exosomes was confirmed to have a positive correlation with osteolytic disease via miR-6791-3p/HDAC4 and that Chinese medicine exerted a potent antimyeloma potential either in clinical practice or experimental studies, to clarify the mechanism that Guizhi Fuling Capsule inhibits the progression of osteopathy by regulating the expression of exosome-derived specific circRNA and subsequently screen the active components of Guizhi Fuling Capsule, further experiments are required to be performed from cell, molecular, and gene expression, including the extraction of exosomes from myeloma cell lines, the establishment of osteolytic mice model with MM, the detection of the osteoclast activity，HDAC / RANKL signaling pathway and mitochondrial function on the level of histology, and the evaluation of trabecular volume and other related indicators by micro CT. All these studies are expected to provide a scientific basis for "Warming Yang and Dissolving Stasis" treatment on the disease.