miRNA-141 Induced Pyroptosis in Intervertebral Disk Degeneration by Targeting ROS Generation and Activating TXNIP/NLRP3 Signaling in Nucleus Pulpous Cells
miRNA-141 Induced Pyroptosis in Intervertebral Disk Degeneration by Targeting ROS Generation and Activating TXNIP/NLRP3 Signaling in Nucleus Pulpous Cells
复制标题
miRNA-141通过靶向ROS生成和激活髓核细胞中TXNIP/NLRP3信号通路诱导椎间盘退行性变热亡
DOI：
10.3389/fcell.2020.00871
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发表时间：
2020-08
影响因子：
5.5
通讯作者：
Qiaolong Xu;Hong-Yuan Xing;Jiaqi Wu;Weishan Chen;Ning Zhang
中科院分区：
文献类型：
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作者：
Qiaolong Xu;Hong-Yuan Xing;Jiaqi Wu;Weishan Chen;Ning Zhang
椎间盘退变过程中细胞凋亡的作用和机制尚不清楚。微小RNA（miRNAs）调节IVD中髓核细胞（NPC）的活力和功能，并且与焦亡相关。我们对正常和退变的髓核（NP）进行了微阵列分析，以评估焦亡的作用，并鉴定IVD退变中的关键miRNAs。我们还评估了NPC中miRNA介导的焦亡的潜在机制。此外，我们在大鼠模型中证明了miRNA对IVD变性的预防作用。与正常组相比，退变组中裂解caspase-1、N-末端gasdermin D（GSDMD）、IL-1 β和IL-18的表达水平明显升高。miRNA-141在变性NP中显着上调。miR-141模拟物抑制NPC的基质合成功能。相比之下，活性氧（ROS）的产生以及TXNIP和NLRP 3的表达被miR-141抑制剂显著下调。此外，miRNA-141抑制剂在体内防止IVD的变性。我们的研究结果表明，miRNA-141通过增加ROS的产生和激活TXNIP/NLRP 3信号转导，诱导NPC中的细胞凋亡和细胞外基质（ECM）催化。miRNA-141调节的焦亡可能是IVD变性的新治疗靶点。
The role and mechanism of pyroptosis in intervertebral disk (IVD) degeneration are unclear. MicroRNAs (miRNAs) regulate the viability and function of nucleus pulposus cells (NPCs) in IVDs and are related to pyroptosis. We performed microarray analyses of normal and degenerated nucleus pulposus (NP) to assess the role of pyroptosis and identify key miRNAs in IVD degeneration. We also evaluated the underlying mechanism of miRNA-mediated pyroptosis in NPCs. In addition, we demonstrated the preventative effects of miRNAs on IVD degeneration in a rat model. The levels of the pyroptosis-related proteins cleaved caspase-1, N-terminal gasdermin D (GSDMD), interleukin (IL)-1β, and IL-18 in the degenerative NP were significantly higher than those in the normal NP. miRNA-141 was significantly upregulated in the degenerated NP. miR-141 mimic suppressed the matrix synthesis function of NPCs. By contrast, reactive oxygen species (ROS) generation, and the expression of TXNIP and NLRP3 were significantly downregulated by an miR-141 inhibitor. Furthermore, the miRNA-141 inhibitor prevented the degeneration of IVDs in vivo. Our findings suggest that miRNA-141 induces pyroptosis and extracellular matrix (ECM) catabolism in NPCs by increasing ROS generation and activating TXNIP/NLRP3 signaling. miRNA-141-regulated pyroptosis may be a novel therapeutic target for IVD degeneration.