NF-κB-miR-10a环路和DDR2-miR-103a通路在类风湿性关节炎中的作用及机制研究

发布时间：2018-04-02 16:11

  本文选题：类风湿性关节炎　切入点：FLS细胞　出处：《第四军医大学》2017年博士论文

【摘要】：类风湿性关节炎(Rheumatoid Arthritis,RA)是一种发病机制不明的全身性自身免疫疾病,主要以慢性、侵袭性、进行性、全身性关节炎症为临床特征。可导致患者关节畸变、活动受限甚至功能丧失,严重影响生活质量,具有较强的致残性。目前认为持续的滑膜炎症和关节邻近骨、软骨损伤是RA的两大关键致病因素。因此,深入研究参与RA滑膜炎症维持和关节邻近骨、软骨破坏的信号转导通路及其调控机制,揭示其中的关键分子与主要环节,对于进一步理解RA的致病机理、改进临床治疗策略具有重要的理论意义与指导价值。成纤维细胞样滑膜细胞(Fibroblast-Like Synovial cells,FLS)是滑膜组织的主要组成部分,RA炎症诱发FLS细胞增生形成的血管翳附着于关节邻近骨、软骨表面,是RA关节邻近骨、软骨破坏的结构基础。RA FLS细胞产生的大量炎症因子及蛋白酶类物质,直接参与了RA滑膜增生及中晚期的关节邻近骨、软骨破坏。因此发现并解析调控RA FLS细胞功能发挥的关键分子及信号通路,可为RA中晚期骨破坏致病机制的阐明提供重要的理论支撑。本研究中,我们以RA FLS细胞在RA致病进程中的功能研究为切入点,一方面,我们发现在RA FLS细胞中,存在TNF-α/NF-κB/YY1/mi R-10a/NF-κB正反馈调节环路,miR-10a在其中扮演了关键分子的角色,通过影响miR-10a,能够有效影响FLS细胞IL-1β、TNF-α和MMPs等炎性因子的产生,继而缓解RA的持续炎症反应。另一方面,结合课题组之前提出的Collagen II-DDR2-MMPs-Collagen II恶性环路的理论,我们发现在RA FLS细胞中,存在DDR2-H19-mi R-103a-IL-15/DKK1这一恶性调节通路,直接参与了RA炎性环境诱发的关节骨重塑进程,加剧了RA患者关节微环境中破骨细胞的分化,打破了关节局部原有的“成骨-破骨平衡”,是RA关节邻近骨、软骨损伤的直接参与者。通过本研究,我们提出并证实了TNF-α/IL-1β/NF-κB/YY1/miR-10a/NF-κB正反馈调节环路在RA FLS细胞介导的RA炎性环境维持中的作用及其调控机制;并在课题组之前研究的基础上,提出并证实了DDR2-H19-miR-103a-IL-15/DKK1通路在RA FLS细胞介导的RA关节骨重塑进程中的作用,初步阐明了上述通路的作用机制。进一步完善和拓展了DDR2在RA关节邻近骨、软骨损伤进程中的重要作用,初步探讨了以miR-10a、DDR2和mi R-103a作为RA治疗新靶点的可能性。
[Abstract]:Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown pathogenesis. It is characterized by chronic, aggressive, progressive and systemic arthritis.It can lead to joint aberration, limited activity and even loss of function, which seriously affects the quality of life and has a strong disability.Persistent synovitis and articular adjacent bone and cartilage injury are considered to be the two key pathogenic factors of RA.Therefore, the study of signal transduction pathway and its regulatory mechanism involved in the maintenance of synovitis and the destruction of adjacent bone and cartilage in synovitis of RA, to reveal the key molecules and main links, is helpful to further understand the pathogenesis of RA.Improving clinical treatment strategy has important theoretical significance and guiding value.Fibroblast-Like Synovial cells (FLSs) is a major component of synovial tissue. The pannus formed by inflammation of FLS cells induced by RA adheres to the adjacent bone and cartilage surface of the joint, and is the adjacent bone of RA joint.The structural basis of cartilage destruction. A large number of inflammatory factors and proteases produced by RA FLS cells are directly involved in synovial hyperplasia of RA and the destruction of articular adjacent bone and cartilage in the middle and late stages of RA.Therefore, the discovery and analysis of the key molecules and signaling pathways regulating the function of RA FLS cells may provide important theoretical support for the elucidation of the pathogenesis of bone destruction in the middle and late stages of RA.In this study, we studied the function of RA FLS cells in the pathogenesis of RA. On the one hand, we found that TNF- 伪 / NF- 魏 B/YY1/mi R-10a / NF- 魏 B positive feedback regulatory loop plays a key role in RA FLS cells.By affecting miR-10a, the production of inflammatory factors such as IL-1 尾 -TNF- 伪 and MMPs in FLS cells can be effectively affected, and then the persistent inflammatory response of RA can be alleviated.On the other hand, based on the theory of Collagen II-DDR2-MMPs-Collagen II malignant loop, we found that DDR2-H19-mi R-103a-IL-15/DKK1 is a malignant regulatory pathway in RA FLS cells, which directly participates in the process of articular bone remodeling induced by RA inflammatory environment.The differentiation of osteoclasts in the microenvironment of RA patients was aggravated, and the "osteoblastic and osteoclast balance" was broken, which was a direct participant in the adjacent bone and cartilage injury of RA joint.In this study, we proposed and confirmed the role and mechanism of TNF- 伪 / IL-1 尾 / NF- 魏 B / Y1 / MiR-10a / NF- 魏 B positive feedback regulatory loop in the maintenance of RA inflammatory environment mediated by RA cells.The role of DDR2-H19-miR-103a-IL-15/DKK1 pathway in the process of RA joint bone remodeling mediated by RA FLS cells was proposed and confirmed, and the mechanism of the pathway was preliminarily elucidated.The important role of DDR2 in the process of articular bone and cartilage injury in RA was further improved and expanded. The possibility of using miR-10a DDR2 and mi R-103a as new targets for RA treatment was preliminarily discussed.
【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R593.22
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本文编号：1701139