2. Academic Validation
  3. BRD9 Inhibition Attenuates Matrix Degradation and Pyroptosis in Nucleus Pulposus by Modulating the NOX1/ROS/NF-κB axis

BRD9 Inhibition Attenuates Matrix Degradation and Pyroptosis in Nucleus Pulposus by Modulating the NOX1/ROS/NF-κB axis

  • Inflammation. 2023 Feb 20. doi: 10.1007/s10753-023-01786-6.
Zhihuai Deng # 1 2,  Yangyang Zhang # 1 2,  Yuanxin Zhu # 1 2,  Jianxiong Zhu 2 3,  Shuangxing Li 1 2,  Zhengqi Huang 1 2,  Tianyu Qin 1 4,  Jiajun Wu 1 2,  Chao Zhang 1 2,  Weijian Chen 2 3,  Dongsheng Huang 1,  Wei Ye 5 6
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Orthopedics, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4 Department of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
  • 5 Department of Spine Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. yewei3@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. yewei3@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 36801999 DOI: 10.1007/s10753-023-01786-6
Abstract

Intervertebral disc degeneration (IDD) is considered to be the leading cause of low back pain (LBP). The progression of IDD is closely related to the inflammatory microenvironment, which results in extracellular matrix degradation and cell death. One of the proteins, which have been shown to participate in the inflammatory response, is the bromodomain-containing protein 9 (BRD9). This study aimed to investigate the role and mechanism of BRD9 in regulating IDD. The tumor necrosis factor-α (TNF-α) was used to mimic the inflammatory microenvironment in vitro. Western blot, RT-PCR, immunohistochemistry, immunofluorescence, and flow cytometry were used to demonstrate the effect of BRD9 inhibition or knockdown on matrix metabolism and Pyroptosis. We found that the expression of BRD9 was upregulated as IDD progressed. BRD9 inhibition or knockdown alleviated TNF-α-induced matrix degradation, Reactive Oxygen Species (ROS) production, and Pyroptosis in rat nucleus pulposus cells. Mechanistically, RNA-seq was used to investigate the mechanism of BRD9 in promoting IDD. Further investigation revealed that BRD9 regulated NOX1 expression. Inhibition of NOX1 could abrogate matrix degradation, ROS production, and Pyroptosis caused by BRD9 overexpression. In vivo, the radiological and histological evaluation showed that the pharmacological inhibition of BRD9 alleviated IDD development in rat IDD model. Our results indicated that BRD9 could promote IDD via the NOX1/ROS/ NF-κB axis by inducing matrix degradation and Pyroptosis. Targeting BRD9 may be a potential therapeutic strategy in treating IDD.

Keywords

BRD9; Intervertebral disc degeneration; NF-κB pathway.; NOX1.

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