Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra‐terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital...

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Published in:Journal of cellular physiology 2020-07, Vol.235 (7-8), p.5736-5749
Main Authors: Hong, Junmin, Li, Shuangxing, Markova, Dessislava Z., Liang, Anjing, Kepler, Christopher K., Huang, Yingjie, Zhou, Jie, Yan, Jiansen, Chen, Weijian, Huang, Dongsheng, Xu, Kang, Ye, Wei
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - genetics
Azepines - pharmacology
BRD4
Cytokines
Degeneration
Degenerative disc disease
Degradation
Disease Models, Animal
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Humans
Inflammasomes
Inflammasomes - drug effects
Inflammation - genetics
Inflammation - pathology
inflammatory cytokine
Inhibition
intervertebral disc degeneration
Intervertebral Disc Degeneration - genetics
Intervertebral Disc Degeneration - pathology
Intervertebral discs
Macrolides - pharmacology
Metabolism
NF-kappa B - genetics
NF‐κB signaling
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLRP3 inflammasome activity
Nuclear Proteins - genetics
Nuclei (cytology)
Nucleus pulposus
Nucleus Pulposus - metabolism
Nucleus Pulposus - pathology
Pathogenesis
Phagocytosis
Polymerase chain reaction
Rats
Signal transduction
Signal Transduction - drug effects
Signaling
Transcription Factor RelA - genetics
Transcription Factors - genetics
Triazoles - pharmacology
Tumor necrosis factor-α
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Summary:An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra‐terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital member of BET family, plays an anti‐inflammatory role in many diseases. However, it remains elusive whether BRD4 plays a similar role in nucleus pulposus (NP) cells and participates in the pathogenesis of intervertebral disc degeneration. The present study aims to observe whether BRD4 inhibition regulates matrix metabolism by controlling autophagy and NLRP3 inflammasome activity. Besides, the relationship was investigated among nuclear factor κB (NF‐κB) signaling, autophagy and NLRP3 inflammasome in NP cells. Here, real‐time polymerase chain reaction, western blot analysis and adenoviral GFP‐LC3 vector transduction in vitro were used, and it was revealed that BRD4 inhibition alleviated the matrix degradation and increased autophagy in the presence or absence of tumor necrosis factor α. Moreover, p65 knockdown or treatment with JQ1 and Bay11‐7082 demonstrated that BRD4 inhibition attenuated NLRP3 inflammasome activity through NF‐κB signaling, while autophagy inhibition by bafilomycin A1 promoted matrix degradation and NLRP3 inflammasome activity in NP cells. In addition, analysis of BRD4 messenger RNA expression in human NP tissues further verified the destructive function of BRD4. Simply, BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through NF‐κB signaling in NP cells. BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through nuclear factor κB signaling in nucleus pulposus cells.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.29508