Therapeutic Potential of Mesenchymal Cell–Derived miRNA-150-5p–Expressing Exosomes in Rheumatoid Arthritis Mediated by the Modulation of MMP14 and VEGF

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial tissue inflammation and joint destruction associated with the activation of angiogenesis. Exosomes, which play a role in cell-to-cell communication as carriers of genetic information, transfer microRNAs (miRNAs or miRs) between cells and have been studied as delivery vehicles for therapeutic molecules. The aim of the current study was to investigate the therapeutic effect of mesenchymal stem cell (MSC)-derived miR-150-5p exosomes on joint destruction in RA. The expression and secretion of miR-150-5p, matrix metalloproteinase (MMP) 14, and vascular endothelial growth factor (VEGF) in RA patients and fibroblast-like synoviocytes (FLS) were examined by quantitative RT-PCR, ELISA, and Western blotting. Immunohistochemistry was used to assess angiogenesis. MSCs were transfected with an miR-150-5p expression plasmid, and MSC-derived exosomes were harvested. The effect of MSC-derived miR-150-5p exosomes (Exo-150) on MMP14 and VEGF expression was examined. The effects of Exo-150 on cell migration and invasion in cytokine-stimulated FLS from RA patients were examined by HUVEC tube formation and transwell assays. The effect of Exo-150 in vivo was examined in a collagen-induced arthritis mouse model. Exo-150 decreased migration and invasion in RA FLS and downregulated tube formation in HUVECs by targeting MMP14 and VEGF. Injection of Exo-150 reduced hind paw thickness and the clinical arthritic scores in collagen-induced arthritis mice. Exo-150 reduced joint destruction by inhibiting synoviocyte hyperplasia and angiogenesis. Exosomes facilitate the direct intracellular transfer of miRNAs between cells and represent a potential therapeutic strategy for RA.

miR‐124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast‐like synoviocytes via targeting PIK3/NF‐κB pathway

“…[20][21][22] The expression profiles of miRNAs of RAFLS differ from those of osteoarthritis FLS. [20][21][22] The expression profiles of miRNAs of RAFLS differ from those of osteoarthritis FLS.…”

“…Recent studies indicated that the imbalance of miRNAs may be involved in the development of RA, which helps improve our understanding of the molecular mechanisms responsible for RA. [20][21][22] The expression profiles of miRNAs of RAFLS differ from those of osteoarthritis FLS. 23 In this study, we focused on miR-124a, which has been reported to play an important role in the pathological process of RA by suppressing the proliferation of RAFLS.…”

Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

“…MSC-derived miR-124a exosomes inhibit the proliferation and migration and promote the apoptosis of fibroblast-like synovial cell lines (66). In addition, exo-miR-150 has been shown to inhibit RA -FLS proliferation and angiogenesis and reduce RA joint destruction by targeting MMP14 and VEGF in rat RASF and CIA rat models (106). In conclusion, miRNA was demonstrated very important roles in the treatment of rheumatoid arthritis not only as the outcome biomarkers but also could be taken as novel drug target to decrease the severity of the patients of rheumatoid arthritis.…”

Mesenchymal stromal cells and their derivatives – putative therapeutics in the management of autoimmune pancreatitis

“…Apoptotic MSCs have demonstrated immunosuppressive properties in mouse models of GVHD [38], and extracellular vesicles have improved the symptoms associated with uveitis/uveoretinitis and type I diabetes mellitus [76]. In addition, exosomes have shown success in ameliorating autoimmune conditions including multiple sclerosis [77], Sjögren's syndrome [78], graft versus host disease [59], systemic lupus erythematosus [79], and rheumatoid arthritis [80]. These results suggest the potential use of derivatives for other autoimmune conditions that lack entirely favorable treatment regimens, such as autoimmune pancreatitis.…”