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 and Hiroshi Asahara ()
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Yoshiaki Ito: Tokyo Medical and Dental University (TMDU)
Tokio Matsuzaki: The Scripps Research Institute
Fumiaki Ayabe: The Scripps Research Institute
Sho Mokuda: The Scripps Research Institute
Ryota Kurimoto: Tokyo Medical and Dental University (TMDU)
Takahide Matsushima: Tokyo Medical and Dental University (TMDU)
Yusuke Tabata: Tokyo Medical and Dental University (TMDU)
Maiko Inotsume: Tokyo Medical and Dental University (TMDU)
Hiroki Tsutsumi: Tokyo Medical and Dental University (TMDU)
Lin Liu: Tokyo Medical and Dental University (TMDU)
Masahiro Shinohara: Tokyo Medical and Dental University (TMDU)
Yoko Tanaka: Tokyo Medical and Dental University (TMDU)
Ryo Nakamichi: The Scripps Research Institute
Keiichiro Nishida: Okayama University Graduate School of Medicine and Dentistry and Pharmaceutical Sciences
Martin K. Lotz: The Scripps Research Institute
Hiroshi Asahara: Tokyo Medical and Dental University (TMDU)

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24460-7

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