Targeting miR-18a sensitizes chondrocytes to anticytokine therapy to prevent osteoarthritis progression

Cell Death & Disease

Lei Liu¹  Tianyu Tao²  Xudong Wang³  Peiqiang Su³  Zhiheng Liao³  Pei Zhao⁴  Yiting Lei⁴  Chengjie Lian⁵ 

[1] Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China;Department of Orthopaedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;Department of Orthopaedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;

DOI  :  10.1038/s41419-020-03155-9

来源: Springer

【 摘 要 】

Inflammation participates in the development of OA and targeting inflammatory signaling pathways is a potential strategy for OA treatment. IL-1β is one of the most important inflammatory factors to trigger the activation of NF-κB signaling and accelerate OA progression, whereas OA patients could hardly benefit from inhibiting IL-1β in clinic, suggesting the importance to further explore the details of OA inflammation. We here showed that expression of miR-18a in chondrocytes was specifically induced in response to IL-1β in vitro as well as in rat model of OA during which NF-κB signaling was involved, and that nuclear-translocated p65 directly upregulated miR-18a expression at transcriptional level. Further, increased miR-18a mediated hypertrophy of chondrocytes, resulting in OA degeneration, by targeting TGFβ1, SMAD2, and SMAD3 and subsequently leading to repression of TGF-β signaling. And the level of serum miR-18a was positively correlated to severity of OA. Interestingly, other than IL-1β, pro-inflammation cytokines involving TNFα could also remarkably upregulate miR-18a via activating NF-κB signaling and subsequently induce chondrocytes hypertrophy, suggesting a pivotal central role of miR-18a in inflammatory OA progression. Thus, our study revealed a novel convergence of NF-κB and TGF-β signaling mediated by miR-18a, and a novel mechanism underlying inflammation-regulated OA dependent of NF-κB/miR-18a/TGF-β axis. Notably, in vivo assay showed that targeting miR-18a sensitized OA chondrocytes to IL-1β inhibitor as targeting IL-1β and miR-18a simultaneously had much stronger inhibitory effects on OA progression than suppressing IL-1β alone. Therefore, the diagnostic and therapeutic potentials of miR-18a for OA were also revealed.

【 授权许可】

CC BY