Use of Targeted Synovial Fibroblasts Improves Experimental Autoimmune Arthritis

Abnormal microRNA (miRNA) expression may contribute to disease development, with evidence supporting its role in rheumatoid arthritis (RA).¹  Synovial fibroblasts with aberrant expression of certain miRNAs are important pathogenic regulators in the joints of patients with RA.  In synovial fibroblasts from patients with RA , levels of gene expression of miR-155-5p are increased while levels of miR-124a are reduced.²   Studies on chondrogenesis in osteoarthritis (OA) have revealed higher expression levels of miRNAs 140-3p and 140-5p.³

Citing recent studies demonstrating that miRNA 140 participates in the regulation of the critical signaling molecule p38 MAPK in RA, Jia-Shiou Peng and colleagues sought to define an intraarticular therapeutic approach using a virus vector to alter levels of miRNA 140 in synovial tissue specimens.⁴

In their study published in Arthritis and Rheumatology, synovial tissue samples were obtained from patients with RA and studied in 2 experimental models of arthritis in mice: T-cell-dependent collagen-induced arthritis (CIA) and T-cell-independent collagen antibody-induced arthritis (CAIA).  Overexpression of miR 140-3p and miR 140-5p was induced in synovial fibroblasts and synovial tissue utilizing lentivirus (LV)-mediated transfer of pre-miR-140 precursor molecules.

At baseline, they found reduced levels of expression of miR 140-3p and miR 140-5p in the RA synovium. Intraarticular delivery of miRNAs 140-3p and 140-5p improved both CIA and CAIA in mice, as demonstrated by reduced arthritis histologic scores and reduced absolute synovial fibroblast densities.

Since tumor necrosis factor (TNF) and interleukin (IL)-1β have been shown to downregulate the expression of both miRNA 140-3p and miRNA 140-5p,³ the authors sought to determine the effects of IL-1β treatment on gene expression. Treatment with IL-1β reduced miR 140-5p expression; overexpression of this molecule could therefore rescue the reduction. The investigators also found that the addition of TNF into synovial fibroblast cultures suppressed miRNA 140-3p expression.

In addition, overexpression of miRNA 140 in the joints of mice with CIA reduced the expression of IL-6, an NF-κB-activated proinflammatory cytokine. Transfection of miR 140-3p and miR 140-5p into synovial fibroblasts also increased cell apoptosis and reduced responses in cellular proliferation. 

It was concluded that intraarticular delivery of miR 140-3p and miR 140-5p can improve autoimmune arthritis in an experimental model by reducing the expression of their target molecules involved in the pathogenesis of inflammation.

Summary and Clinical Applicability

 

Targeted fibroblasts, after intraarticular delivery of miR 140-3p and miR 140-5p miRNAs, can improve autoimmune arthritis in an experimental model by reducing the expression of their target molecules. These findings may open a window into possible future pharmacologic development of molecular-based therapies in RA.

Reference

1.       Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 2014;13:622-638.

2.       Apparailly F, Jorgensen C. siRNA-based therapeutic approaches for rheumatic diseases. Nat Rev Rheumatol. 2013;9:56-62.

3.       Karlsen TA, Jakobsen RB, Mikkelsen TS, Brinchmann JE. MicroRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev. 2014;23:290-304.

4.       Peng JS, Chen SY, Wu CL, et al. Amelioration of experimental autoimmune arthritis through targeting of synovial fibroblasts by intraarticular delivery of microRNAs 140-3p and 140-5p. Arthritis Rheumatol. 2016;68(2):370-381.