MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis

Mol Ther. 2017 Dec 6;25(12):2676-2688. doi: 10.1016/j.ymthe.2017.08.009. Epub 2017 Aug 19.

Abstract

Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.

Keywords: PI3K/Akt/mTOR signaling pathway; microRNA; osteoarthritis.

MeSH terms

  • Aged
  • Animals
  • Biomarkers
  • Case-Control Studies
  • Cell Proliferation
  • Chondrocytes / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Down-Regulation
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Genes, Reporter
  • Genetic Therapy
  • Humans
  • Male
  • Mice
  • MicroRNAs*
  • Middle Aged
  • Osteoarthritis / genetics*
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy
  • Phosphatidylinositol 3-Kinases / genetics
  • Plasmids / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Reproducibility of Results
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Transfection

Substances

  • Biomarkers
  • MIRN218 microRNA, human
  • MicroRNAs
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • PIK3C2A protein, human
  • Proto-Oncogene Proteins c-akt