当前位置: X-MOL 学术Osteoarthr. Cartil. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Alarmins S100A8/A9 promote intervertebral disc degeneration and inflammation-related pain in a rat model through toll-like receptor-4 and activation of the NF-κB signaling pathway
Osteoarthritis and Cartilage ( IF 7 ) Pub Date : 2022-04-08 , DOI: 10.1016/j.joca.2022.03.011
J Zheng 1 , J Wang 1 , H Liu 1 , F Chen 1 , H Wang 1 , S Chen 1 , J Xie 1 , Z Zheng 1 , Z Li 2
Affiliation  

Objective

The molecules released from cells undergoing necrosis are recognized as alarmins, and S100A8/9, a typical alarmin, is associated with several inflammation-related diseases. This study was to investigate the molecular role of S100A8/A9 on the process of intervertebral disc degeneration (IVDD) and inflammation-related pain.

Methods

The expression pattern of S100A8/A9 in different degenerated human nucleus pulposus (NP) tissues were measured by Real-time quantitative reverse transcription PCR (RT-qPCR) and immunohistochemical (IHC). The effects of S100A8/A9 on matrix production were assessed by RT-qPCR, western blotting, and cell immunofluorescence. Involvement of TLR4 and NF-κB signaling pathways were studied by pharmachemical inhibitors and small interfering RNAs (siRNAs). The development of degenerative and pain features in the IVDD model were examed by IHC and pain-behavior testing.

Results

The expression of S100A8/A9 was significantly elevated in severely degenerated human NP tissue with similar expression pattern of TNF-α. In NP cells, S100A8/A9 increased MMP-3/13, TNF-α, IL-6 expression and inhibited aggrecan and collagen II expression. RT-qPCR and western blotting showed that the regulatory effects of S100A8/A9 on IVD were TLR4 dependent. Pharmacological inhibition or siRNA knockdown of the NF-κB signaling attenuated S100A8/A9-induced upregulation of MMP-3/13, TNF-α and IL-6. In vivo, S100A9 inhibitor treatment inhibited disc-puncture induced IVDD and inflammation-related pain.

Conclusions

This study showed that S100A8/A9 bound to TLR4 and increased the expression of MMPs, TNF-α, and IL-6 through NF-κB signaling pathways in NP cells. Furthermore, S100A8/A9 inhibitor could prevent development of IVDD and inflammation-related pain in the rat model.



中文翻译:

警报素 S100A8/A9 通过 toll 样受体 4 和激活 NF-κB 信号通路促进大鼠模型中的椎间盘退变和炎症相关疼痛

客观的

发生坏死的细胞释放的分子被认为是警报素,而典型的警报素 S100A8/9 与几种炎症相关疾病有关。本研究旨在探讨 S100A8/A9 在椎间盘退变 (IVDD) 和炎症相关疼痛过程中的分子作用。

方法

通过实时定量逆转录聚合酶链反应 (RT-qPCR) 和免疫组织化学 (IHC) 测量 S100A8/A9 在不同退化的人髓核 (NP) 组织中的表达模式。通过 RT-qPCR、蛋白质印迹和细胞免疫荧光评估 S100A8/A9 对基质产生的影响。通过药物化学抑制剂和小干扰 RNA (siRNA) 研究了 TLR4 和 NF-κB 信号通路的参与。通过 IHC 和疼痛行为测试检查 IVDD 模型中退行性和疼痛特征的发展。

结果

S100A8/A9 的表达在严重退化的人 NP 组织中显着升高,具有相似的 TNF-α 表达模式。在 NP 细胞中,S100A8/A9 增加 MMP-3/13、TNF-α、IL-6 的表达并抑制聚集蛋白聚糖和胶原蛋白 II 的表达。RT-qPCR 和蛋白质印迹显示 S100A8/A9 对 IVD 的调节作用是 TLR4 依赖性的。NF-κB 信号传导的药理抑制或 siRNA 敲低减弱了 S100A8/A9 诱导的 MMP-3/13、TNF-α 和 IL-6 的上调。在体内,S100A9 抑制剂治疗抑制椎间盘穿刺诱导的 IVDD 和炎症相关疼痛。

结论

本研究表明,S100A8/A9 与 TLR4 结合,并通过 NF-κB 信号通路增加 NP 细胞中 MMP、TNF-α 和 IL-6 的表达。此外,S100A8/A9 抑制剂可以预防大鼠模型中 IVDD 和炎症相关疼痛的发展。

更新日期:2022-04-08
down
wechat
bug