title: miR-573 is a negative regulator in the pathogenesis of rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. Our previous study demonstrated an increased expression of thioredoxin domain containing 5 (TXNDC5) in the synovial tissues of RA, and its overexpression was implicated in RA pathology. Although TXNDC5 variation is linked to genetic susceptibility to RA, the regulation of its abnormal expression has not been well defined. Here, we show that TXNDC5 is directly targeted by microRNA (miR)-573, and TXNDC5, in turn, mediates the suppressive effect of miR-573 on the invasion of synovial fibroblasts of RA (RASFs). miR-573 overexpression suppressed the expression of interleukin 6 (IL-6) and cyclooxygenase 2 in RASFs, as well as the production of tumor necrosis factor-alpha and interleukin-1 beta by activated THP-1 cells in response to lipopolysaccharide (LPS) stimulation. Moreover, treatment with conditioned medium of RASFs transfected with miR-573 mimic inhibited the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Of note, epidermal growth factor receptor and Toll-like receptor 2 were validated as new direct targets of miR-573, and mediate the regulation of miR-573 on IL-6 production as well as the angiogenesis of HUVECs. In addition, exogenous miR-573 expression suppressed the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3, and phosphatidylinositol-3 kinase/activate protein kinase B in RASFs in response to LPS. Indeed, MAPK signaling was essential to ensure the function of miR-573. Taken together, our study points toward the protective roles of miR-573 in the pathological process of RA and suggests a potential target in the treatment of RA.
authors.affiliation: Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Song
authors.affiliation: Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of pathology, Linyi People's Hospital Linyi People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of pathology, Linyi People's Hospital Linyi People's Republic of China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, People's Republic of China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Pan
authors.affiliation: Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C585063:MIRN573 microRNA, human; D035683:MicroRNAs; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D019704:Protein Disulfide-Isomerases; C480743:TXNDC5 protein, human