期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24460-7
关键词
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资金
- Japan Agency for Medical Research and Development (Core Research for Evolutional Science and Technology) [JP15gm0410001, JP20gm0810008]
- Naito Foundation
- Japan Society for the Promotion of Science (Kakenhi) [18K19603, 19KK0227, 20H00547, 17H04155]
- National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR050631]
- Grants-in-Aid for Scientific Research [20H00547, 19KK0227, 18K19603, 17H04155] Funding Source: KAKEN
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2 alpha and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
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-2 alpha (HIF-2 alpha), 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-2 alpha 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. Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2 alpha and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
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