The Study Of The Function And Mechanism Of NF-?B-miR-10a Loop And DDR2-miR-103a Pathway In Rheumatoid Arthritis

Rheumatoid Arthritis(RA),is a kind of severe and systemic autoimmune diseases.The main clinical manifestation of RA is chronic,aggressive and progressive joint inflammation.If patients with RA do not receive reasonable treatment in time,it will ultimately cause joint distortion,and moving restriction,even lead to permanent disability.Nowadays,it has been reported that the persistent inflammation of synovial tissue and the damage of bone/cartilage are two major pathogenic factors of RA.Therefore,it is urgent to get better understanding of the mechanism and regulatory network of synovial inflammation and bone/cartilage destruction in RA,especially the key molecules and main pathways in those pathological processes.The answer of these problems may not only help laying theoretical foundations in deeper understanding of this disease,but also provide potential clinical strategies of RA treatment.The pannus,which attaches to the joint cartilage surface,is the basic structure in patients with RA.And the proliferation of synovial tissue will cause over secreted MMPs and protein enzymes to degrade the bone and cartilage.Fibroblasts synovial cells(FLS)is the main component of synovial tissue,which produces a large number of inflammatory factors and protein enzymes in the whole pathological process of RA.So if the key molecules and signaling pathways of RA FLS were found,it will be conducive to clarify the mechanism of synovial inflammation and bone/cartilage destruction.In this study,we aimed to investigate the biological changes of RA FLS.On the one hand,we found that there is a positive feedback loop in RA FLS,which is TNF-? /NF-?B/YY1/miR-10a/NF-?B loop.MiR-10 a is the key molecule in the loop,and higher miR-10 a expression will cause less production of inflammatory cytokines,such as IL-1?,TNF-? and MMPs and relieve sustained inflammation of RA.On the other hand,we found another vicious regulation pathway in RA FLS,which is DDR2-H19-miR-103a-IL-15/DKK1 pathway.It is directly involved in the bone remodeling process induced by RA inflammatory environment,which increases the osteoclast differentiation in RA.The effects and mechanism of TNF-?/NF-?B/YY1/miR-10a/NF-?B positive feedback loop was found and proved gradually through the investigation of the thesis.And we also proposed and proved the effects of DDR2-H19-miR-103a-IL-15/DKK1 pathway in bone remolding process of RA.In addition,the possibility to make miR-10 a,DDR2 or miR-103 a as potential therapeutic targets in RA treatment was also evaluated in our study.