Exp Mol Med.  2017 Aug;49(8):e363. 10.1038/emm.2017.108.

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

• Hong BK
• You S
• Yoo SA
• Park D
• Hwang D
• Cho CS
• Kim WU

• KMID: 2389291
• DOI: http://doi.org/10.1038/emm.2017.108

Abstract

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.

MeSH Terms

Arthritis, Rheumatoid*
Fibroblasts*
Insulin-Like Growth Factor Binding Protein 5
Interleukin-6
Luciferases
MicroRNAs
Osteoarthritis
Phenotype*
RNA, Messenger
Semaphorin-3A
Synovial Fluid
Insulin-Like Growth Factor Binding Protein 5
Interleukin-6
Luciferases
MicroRNAs
RNA, Messenger
Semaphorin-3A