期刊
MOLECULAR THERAPY
卷 29, 期 1, 页码 308-323出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2020.09.002
关键词
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资金
- National Key R&D Program of China [2018YFC1105200]
- Key Research and Development Plan in Zhejiang Province [2018C03060]
- National Natural Science Foundation of China [81772387, 81802680]
- Major Projects for Industry-University-Research Collaborative Innovation of Science, and Technology Plan of Guangzhou City [201604020095]
The study identified a critical role of circPDE4D in maintaining the extracellular matrix during osteoarthritis progression by acting as a sponge for miR-103a-3p and regulating FGF18 expression. Targeting the circPDE4D-miR-103a-3p-FGF18 axis may provide a promising approach for osteoarthritis therapy.
Osteoarthritis (OA) is a common, age-related, and painful disease characterized by cartilage destruction, osteophyte formation, and synovial hyperplasia. This study revealed that circPDE4D, a circular RNA derived from human linear PDE4D, plays a critical role in maintaining the extracellular cellular matrix (ECM) during OA progression. circPDE4D was significantly downregulated in OA cartilage tissues and during stimulation with inflammatory cytokines. The knockdown of circPDE4D predominantly contributed to Aggrecan loss and the upregulation of matrix catabolic enzymes, including MMP3, MMP13, ADAMTS4, and ADAMTS5, but not proliferation or apoptosis. In a murine model of destabilization of the medial meniscus (DMM), the intraarticular injection of circPDE4D alleviated DMM-induced cartilage impairments. Mechanistically, we found that circPDE4D exerted its effect by acting as a sponge for miR-103a-3p and thereby regulated FGF18 expression, which is a direct target of miR-103a-3p. In conclusion, our findings highlight a novel protective role of circPDE4D in OA pathogenesis and indicate that the targeting of the circPDE4D-miR-103a-3p-FGF18 axis might provide a potential and promising approach for OA therapy.
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