MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis

作者：Lu, Jun^*; Ji, Ming-liang; Zhang, Xue-jun; Shi, Pei-liang; Wu, Hao; Wang, Chen; Im, Hee-Jeong

来源：Molecular Therapy, 2017, 25(12): 2676-2688.

DOI：10.1016/j.ymthe.2017.08.009

• WIDE DNA METHYLATION
• SIGNIFICANT EPIGENOMIC CHANGES
• KNEE OSTEOARTHRITIS
• ARTICULAR-CARTILAGE
• SUBCHONDRAL BONE
• CHONDROCYTES
• EXPRESSION
• HIP
• CLASSIFICATION
• SURVIVAL

Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.

• 出版日期2017-12-6
• 单位南京大学; 东南大学