title: Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts.
abstract: Activated synovial fibroblasts in rheumatoid arthritis (RASF) play a critical role in the pathology of rheumatoid arthritis (RA). Recent studies suggested that deregulation of microRNAs (miRs) affects the development and progression of RA. Therefore, we aimed to identify de-regulated miRs in RASF and to identify target genes that may contribute to the aggressive phenotype of RASF. Quantitative real-time PCR revealed a marked downregulation of miR-188-5p in synovial tissue samples of RA patients as well as in RASF. Exposure to the cytokine interleukine-1β lead to a further downregulation of miR-188-5p expression levels compared to control cells. Re-expression of miR-188-5p in RASF by transient transfection significantly inhibited cell migration. However, miR-188-5p re-expression had no effects on glycosaminoglycan degradation or expression of repellent factors, which have been previously shown to affect the invasive behavior of RASF. In search for target genes of miR-188-5p in RASF we performed gene expression profiling in RASF and found a strong regulatory effect of miR-188-5p on the hyaluronan binding protein KIAA1199 as well as collagens COL1A1 and COL12A1, which was confirmed by qRT-PCR. In silico analysis revealed that KIAA1199 carries a 3'UTR binding site for miR-188-5p. COL1A1and COL12A1 showed no binding site in the mRNA region, suggesting an indirect regulation of these two genes by miR-188-5p. In summary, our study showed that miR-188-5p is down-regulated in RA in vitro and in vivo, most likely triggered by an inflammatory environment. MiR-188-5p expression is correlated to the activation state of RASF and inhibits migration of these cells. Furthermore, miR-188-5p is directly and indirectly regulating the expression of genes, which may play a role in extracellular matrix formation and destruction in RA. Herewith, this study identified potential novel therapeutic targets to inhibit the development and progression of RA.
authors.affiliation: Institute of Pathology, University Hospital Regensburg Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Ruedel
authors.affiliation: Institute for Biochemistry, Biochemistry and Molecular Medicine, Emil-Fischer Zentrum, Friedrich-Alexander-University of Erlangen-Nürnberg Fahrstraße 17, D-91054 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University Hospital of Erlangen Krankenhausstr.12, D-91054 Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schubert
authors.affiliation: Institute of Pathology, University Hospital Regensburg Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Hofmeister
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.affiliation: Institute for Biochemistry, Biochemistry and Molecular Medicine, Emil-Fischer Zentrum, Friedrich-Alexander-University of Erlangen-Nürnberg Fahrstraße 17, D-91054 Erlangen, Germany.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D020413:3' Untranslated Regions; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024082:Collagen Type XII / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D006821:Hyaluronoglucosaminidase; D053583:Interleukin-1beta / Q000494:pharmacology; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C547160:COL12A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024082:Collagen Type XII; C508585:IL1B protein, human; D053583:Interleukin-1beta; C584093:MIRN188 microRNA, human; D035683:MicroRNAs; D011506:Proteins; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase
keywords: KIAA1199; Rheumatoid arthritis; miR-188-5p; synovial fibroblasts