miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis

Bioengineered. 2021 Dec;12(2):11225-11238. doi: 10.1080/21655979.2021.1995580.

Abstract

miRNAs are broad participants in vertebrate biological processes, and they are also the major players in pathological processes. miR-125a-5p was recently found a modulator in the progression of osteoarthritis (OA). Our study was aimed to explore the role and underlying mechanisms of miR-125a-5p-abundant exosomes derived from mesenchymal stem cells (MSC) on OA progression. We separated bone marrow mesenchymal stem cells (BMSCs) as well as the exosomes from traumatic OA patients. The immunofluorescence and cartilage staining were implemented for the observation and the assessment on endocytosis of chondrocytes and exosomal miR-125a-5p efficacy to cartilage degradation. Dual luciferase reporter assay was performed to verified the relationship between miR-125a-5p and E2F2. Then, the function of exosomal miR-125a-5p were examined on chondrocyte degeneration in vitro and in vivo. Our findings indicated that E2F2 expression was elevated while the miR-125a-5p was down in traumatic OA cartilage tissue, showing a negative correlation of the former and the latter. miR-125a-5p targets E2F2 in traumatic OA cartilage tissue and leads to the down-expression of E2F2. The E2F2 expression in chondrocytes was decreased after internalization of exosomes. We additionally found that BMSCs-derived exosomes were rich in miR-125a-5p content and chondrocytes can have it internalized. miR-125a-5p is endowed with a trait of accelerating chondrocytes migration, which is going along with the up-expressions of Collagen II, aggrecan and SOX9 and the down-expression of MMP-13 in vitro. Besides that, the mice model with post-traumatic OA turned out that exosomal miR-125a-5p might beget an alleviation in chondrocyte extracellular matrix degradation. All these outcomes revealed that BMSCs-derived exosomal miR-125a-5p is a positive regulator for chondrocyte migration and inhibit cartilage degeneration We thus were reasonable to believe that transferring of exosomal miR-125a-5p is a prospective strategy for OA treatment.

Keywords: E2f2; Traumatic osteoarthritis; bone marrow mesenchymal stem cells; chondrocyte degeneration; exosomes; miR-125a-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aggrecans / metabolism
  • Animals
  • Base Sequence
  • Cell Movement / genetics
  • Chondrocytes / pathology*
  • Collagen Type II / metabolism
  • E2F2 Transcription Factor / metabolism*
  • Exosomes / metabolism*
  • Exosomes / ultrastructure
  • Female
  • Humans
  • Male
  • Matrix Metalloproteinase 13
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Osteoarthritis / complications
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology*
  • SOX9 Transcription Factor / metabolism
  • Wounds and Injuries / complications
  • Wounds and Injuries / genetics*
  • Wounds and Injuries / pathology

Substances

  • Aggrecans
  • Collagen Type II
  • E2F2 Transcription Factor
  • MIRN125 microRNA, human
  • MicroRNAs
  • SOX9 Transcription Factor
  • MMP13 protein, human
  • Matrix Metalloproteinase 13

Grants and funding

This study was supported by Basic Public Welfare Research Project of Zhejiang Province (Grant No.LGF19H060001), Research on Public Welfare Technology Application Projects of Zhejiang Province (Grant No.LGF19H060009), and the Medical Science and Technology Program of Zhejiang Province (2018KY894).