MicroRNA-143 and -145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis

Fibroblast-like synoviocytes (FLSs) constitute a major cell subset of rheumatoid arthritis (RA) synovia. Dysregulation of microRNAs (miRNAs) has been implicated in activation and proliferation of RA-FLSs. However, the functional association of various miRNAs with their targets that are characteristic of the RA-FLS phenotype has not been globally elucidated. In this study, we performed microarray analyses of miRNAs and mRNAs in RA-FLSs and osteoarthritis FLSs (OA-FLSs), simultaneously, to validate how dysregulated miRNAs may be associated with the RA-FLS phenotype. Global miRNA profiling revealed that miR-143 and miR-145 were differentially upregulated in RA-FLSs compared to OA-FLSs. miR-143 and miR-145 were highly expressed in independent RA-FLSs. The miRNA-target prediction and network model of the predicted targets identified insulin-like growth factor binding protein 5 (IGFBP5) and semaphorin 3A (SEMA3A) as potential target genes downregulated by miR-143 and miR-145, respectively. IGFBP5 level was inversely correlated with miR-143 expression, and its deficiency rendered RA-FLSs more sensitive to TNFα stimulation, promoting IL-6 production and NF-κB activity. Moreover, SEMA3A was a direct target of miR-145, as determined by a luciferase reporter assay, antagonizing VEGF165-induced increases in the survival, migration and invasion of RA-FLSs. Taken together, our data suggest that enhanced expression of miR-143 and miR-145 renders RA-FLSs susceptible to TNFα and VEGF165 stimuli by downregulating IGFBP5 and SEMA3A, respectively, and that these miRNAs could be therapeutic targets. Enhanced expression of two microRNAs contributes to the development of rheumatoid arthritis in specialized cells that line joints. Wan-Uk Kim at the Catholic University of Korea in Seoul, South Korea, and colleagues analysed expression levels of non-coding microRNAs in cells known as fibroblast-like synoviocytes (FLSs), which are found inside joints and have a crucial role in chronic inflammatory disease. The researchers compared levels of these regulatory RNAs in FLSs from patients with rheumatoid arthritis, which is caused by autoimmunity, and those with osteoarthritis, which is caused by wear and tear. They found that only FLSs from rheumatoid-arthritis patients had elevated levels of microRNA-143 and microRNA-145. They also showed that these microRNAs control the expression of genes involved in promoting inflammation, cell survival and cell migration. These microRNAs could offer therapeutic targets for future drug development.