| Rheumatoid arthritis(RA)'s main feature of this autoimmune disease is synovitis.inflammation.The destruction of RA articular cartilage is closely related to the process of bone remodeling induced by synovial inflammation,and repeated inflammation of arthritis can lead to joint destruction and eventually disability with high morbidity.Therefore,comprehensive analysis mediated RA synovial inflammation of the joints of adjacent bone and cartilage damage related signal pathways,and regulating mechanism of important molecules,on the one hand,to new cognitive RA disease occurrence and evolution of the relevant theoretical basis,on the other hand for better clinical treatment of RA disease provides a new drug targets.Previous studies have shown that T and B lymphocytes are involved in abnormal immune responses and promote the development of RA.However,fibroblast-like synovial cells(FLS)located in the synovial lining layer have recently become a research hotspot.The compensatory hyperplasia and migration of FLS caused by joint damage promote pannus formation and bone destruction in RA,and cytokines,chemokines,matrix metalloproteinases and matrix metal degrading enzymes that secreted by FLS can promote itself to enter the vicious cycle of proliferation and migration,bone and cartilage destruction,which eventually leads to disability.Thus,elucidating how the function ofFLS changes has important guiding significance for revealing the pathogenic mechanism of RA.Tumour Necrosis Factor ?(TNF-?)has a variety of biological activities,it can regulate cell recruitment,proliferation,death and immune response,etc.In RA,excessive production of TNF-? is one of the key factors to drive inflammation resonpnses and joint destruction,;it also regulates matrix degradation and osteoclast differentiation.Although blocking agents like TNF-? neutralizing monoclonal antibodies and soluble receptors have been widely used in clinical treatment of RA,the detailed molecular mechanism of TNF-?in RA is still largely unkonwn.Micro RNAs(miRNAs),as non-coding RNAs,play important roles in various diseases by regulating downstream target genes.More than 300 miRNAs that were differentially expressed in RA and Osteoarthritis(OA)patients were previously screened in our group.In this study,we used RA FLS as an object to investigate the pathophysiology of RA and revealed the molecular mechanisms by which mi R-103 a participate in the development of RA by regulating the biological behavior of FLS cells.We found that mi R-103 a was significantly down-regulated in RA FLS,and this down-regulation was dependent on the NF-?B pathway activated by TNF-?;the latter inhibited activation of transcription factors contributes to increased mi R-103 a levels Yin Yang1(YY1).Further studies showed that TAK1 and DKK1 are target genes of mi R-103 a,and down-regulated mi R-103 a can greatly promote the expression levels of both target genes.TAK1,as an upstream key regulator of NF-?B signaling pathway,can promote the activation of NF-?B.On one hand,this pathway can up-regulate the expression the inflammatory cytokines and MMPs;on the other,it can promote the proliferation,invasion and migration of FLS.DKK1 is a regulatory factor of osteoclast development and differentiation.Up-regulation of DKK1 in FLS by mi R-103 a can directly promote the differentiation of myeloid monocyte-derived osteoclasts and thus participate in bone destruction in RA.Through this study,we propose and confirm that the regulatory circuit of TNF-??NF-?B??YY1??mi R-103a??TAK1??NF-?B? in FLS mediated themicroenvironment inflammatory response;whereas the TNF-??NF-?B??YY1??mi R-103a??DKK1? pathway mediated bone destruction in RA.Taken together,this study clarified the molecular mechanism of mi R-103a-mediated TNF-?regulation of inflammatory response and bone destruction in RA.Our data provides new insights for the pathogenic mechanism of TNF-? and clinical application of antagonists,and also indicates that mi R-103 a may be a potential target for RA diagnosis and therapy. |
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