Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis

Nat Commun. 2021 Jul 6;12(1):4148. doi: 10.1038/s41467-021-24460-7.


Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage / metabolism*
  • Cartilage, Articular / metabolism
  • Chondrocytes / metabolism
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation
  • Homeostasis*
  • Humans
  • Hypoxia / metabolism*
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Osteoarthritis / genetics
  • SOX9 Transcription Factor
  • Transcription Factors / metabolism*


  • MIRN455 microRNA, human
  • MIRN455 microRNA, mouse
  • MicroRNAs
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Transcription Factors