本文選題：類風(fēng)濕性關(guān)節(jié)炎　切入點：FLS細胞　出處：《第四軍醫(yī)大學(xué)》2017年博士論文

【摘要】：類風(fēng)濕性關(guān)節(jié)炎(Rheumatoid Arthritis,RA)是一種發(fā)病機制不明的全身性自身免疫疾病,主要以慢性、侵襲性、進行性、全身性關(guān)節(jié)炎癥為臨床特征。可導(dǎo)致患者關(guān)節(jié)畸變、活動受限甚至功能喪失,嚴重影響生活質(zhì)量,具有較強的致殘性。目前認為持續(xù)的滑膜炎癥和關(guān)節(jié)鄰近骨、軟骨損傷是RA的兩大關(guān)鍵致病因素。因此,深入研究參與RA滑膜炎癥維持和關(guān)節(jié)鄰近骨、軟骨破壞的信號轉(zhuǎn)導(dǎo)通路及其調(diào)控機制,揭示其中的關(guān)鍵分子與主要環(huán)節(jié),對于進一步理解RA的致病機理、改進臨床治療策略具有重要的理論意義與指導(dǎo)價值。成纖維細胞樣滑膜細胞(Fibroblast-Like Synovial cells,FLS)是滑膜組織的主要組成部分,RA炎癥誘發(fā)FLS細胞增生形成的血管翳附著于關(guān)節(jié)鄰近骨、軟骨表面,是RA關(guān)節(jié)鄰近骨、軟骨破壞的結(jié)構(gòu)基礎(chǔ)。RA FLS細胞產(chǎn)生的大量炎癥因子及蛋白酶類物質(zhì),直接參與了RA滑膜增生及中晚期的關(guān)節(jié)鄰近骨、軟骨破壞。因此發(fā)現(xiàn)并解析調(diào)控RA FLS細胞功能發(fā)揮的關(guān)鍵分子及信號通路,可為RA中晚期骨破壞致病機制的闡明提供重要的理論支撐。本研究中,我們以RA FLS細胞在RA致病進程中的功能研究為切入點,一方面,我們發(fā)現(xiàn)在RA FLS細胞中,存在TNF-α/NF-κB/YY1/mi R-10a/NF-κB正反饋調(diào)節(jié)環(huán)路,miR-10a在其中扮演了關(guān)鍵分子的角色,通過影響miR-10a,能夠有效影響FLS細胞IL-1β、TNF-α和MMPs等炎性因子的產(chǎn)生,繼而緩解RA的持續(xù)炎癥反應(yīng)。另一方面,結(jié)合課題組之前提出的Collagen II-DDR2-MMPs-Collagen II惡性環(huán)路的理論,我們發(fā)現(xiàn)在RA FLS細胞中,存在DDR2-H19-mi R-103a-IL-15/DKK1這一惡性調(diào)節(jié)通路,直接參與了RA炎性環(huán)境誘發(fā)的關(guān)節(jié)骨重塑進程,加劇了RA患者關(guān)節(jié)微環(huán)境中破骨細胞的分化,打破了關(guān)節(jié)局部原有的“成骨-破骨平衡”,是RA關(guān)節(jié)鄰近骨、軟骨損傷的直接參與者。通過本研究,我們提出并證實了TNF-α/IL-1β/NF-κB/YY1/miR-10a/NF-κB正反饋調(diào)節(jié)環(huán)路在RA FLS細胞介導(dǎo)的RA炎性環(huán)境維持中的作用及其調(diào)控機制;并在課題組之前研究的基礎(chǔ)上,提出并證實了DDR2-H19-miR-103a-IL-15/DKK1通路在RA FLS細胞介導(dǎo)的RA關(guān)節(jié)骨重塑進程中的作用,初步闡明了上述通路的作用機制。進一步完善和拓展了DDR2在RA關(guān)節(jié)鄰近骨、軟骨損傷進程中的重要作用,初步探討了以miR-10a、DDR2和mi R-103a作為RA治療新靶點的可能性。
[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- 偽 / 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- 偽 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- 偽 / 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.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R593.22
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本文編號：1701139