miR-34a in extracellular vesicles from bone marrow mesenchymal stem cells reduces rheumatoid arthritis inflammation via the cyclin I/ATM/ATR/p53 axis

J Cell Mol Med. 2021 Feb;25(4):1896-1910. doi: 10.1111/jcmm.15857. Epub 2021 Jan 19.


Extracellular vesicles (Evs) participate in the development of rheumatoid arthritis (RA), but the mechanisms remain unclear. This study aimed to determine the mechanism by which microRNA-34a (miR-34a) contained in bone marrow mesenchymal stem cell (BM-MSC)-derived Evs functions in RA fibroblast-like synoviocytes (RA-FLSs). BM-MSC-derived Evs and an Evs inhibitor were extracted. A rat model of RA was established. miR-34a gain- and loss-of-function experiments were performed, and the inflammation in rat synovial fluid and tissues was detected. The role of miR-34a in RA-FLSs was also measured in vitro. The target gene of miR-34a was predicted using the online software TargetScan and identified using a dual-luciferase reporter gene assay, and the activation of the ATM/ATR/p53 signalling pathway was assessed. BM-MSC-derived Evs mainly elevated miR-34a expression, which reduced RA inflammation in vivo and inhibited RA-FLS proliferation and resistance to apoptosis in vitro, while inhibited miR-34a expression enhanced RA development. In addition, miR-34a could target cyclin I to activate the ATM/ATR/p53 signalling pathway, thus inhibiting abnormal RA-FLS growth and RA inflammation. Our study showed that miR-34a contained in BM-MSC-derived Evs could reduce RA inflammation by inhibiting the cyclin I/ATM/ATR/p53 signalling pathway.

Keywords: ATM/ATR/p53 signalling pathway; Cyclin I; MicroRNA-34a; extracellular vesicles; inflammation; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Biomarkers
  • Biopsy
  • Cells, Cultured
  • Cyclin I / metabolism
  • Extracellular Vesicles / metabolism*
  • Gene Expression Regulation*
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Rats
  • Signal Transduction*
  • Synoviocytes / metabolism
  • Synoviocytes / pathology
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers
  • Cyclin I
  • MicroRNAs
  • Tumor Suppressor Protein p53