TY - JOUR
T1 - Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
AU - Ito, Yoshiaki
AU - Matsuzaki, Tokio
AU - Ayabe, Fumiaki
AU - Mokuda, Sho
AU - Kurimoto, Ryota
AU - Matsushima, Takahide
AU - Tabata, Yusuke
AU - Inotsume, Maiko
AU - Tsutsumi, Hiroki
AU - Liu, Lin
AU - Shinohara, Masahiro
AU - Tanaka, Yoko
AU - Nakamichi, Ryo
AU - Nishida, Keiichiro
AU - Lotz, Martin K.
AU - Asahara, Hiroshi
N1 - Funding Information:
We are grateful to all members of the Asahara Lab for their technical help and discussion. We thank S. Yamashita for his technical support in Sox9 downstream miRNA analysis and T. Kato for her technical support in generating the genome editing mice. We also appreciate Life Science Editors (https://www.lifescienceeditors.com) for English proofreading support. This research was supported by the Japan Agency for Medical Research and Development (Core Research for Evolutional Science and Technology grants JP15gm0410001 and JP20gm0810008), the Naito Foundation, the Japan Society for the Promotion of Science (Kakenhi grants 18K19603, 19KK0227, 20H00547, and 17H04155), and National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants AR050631) (H.A.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85110960814&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110960814&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-24460-7
DO - 10.1038/s41467-021-24460-7
M3 - Article
C2 - 34230481
AN - SCOPUS:85110960814
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4148
ER -
