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

Yoshiaki Ito, Tokio Matsuzaki, Fumiaki Ayabe, Sho Mokuda, Ryota Kurimoto, Takahide Matsushima, Yusuke Tabata, Maiko Inotsume, Hiroki Tsutsumi, Lin Liu, Masahiro Shinohara, Yoko Tanaka, Ryo Nakamichi, Keiichiro Nishida, Martin K. Lotz, Hiroshi Asahara

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number4148
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis'. Together they form a unique fingerprint.

Cite this