Advanced oxidation protein products induce annulus fibrosus cell senescence through a NOX4-dependent, MAPK-mediated pathway and accelerate intervertebral disc degeneration

PeerJ

article

Xiangheng Dai¹  Yu Chen¹  Zihan Yu¹  Congrui Liao¹  Zhongyuan Liu¹  Jianting Chen¹  Qian Wu¹ 

[1] Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University

关键词: Senescence;    Intervertebral disc degeneration;    Advanced oxidized protein products;    Inflammation associated with senescence;   

DOI  :  10.7717/peerj.13826

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundIntervertebral disc degeneration (IVDD) is closely associated with senescence. Annulus fibrosus (AF) cell senescence is a crucial driver of AF tissue tearing and fissures, thereby exacerbating IVDD. Increased advanced oxidative protein products (AOPPs) were found in human degenerative discs and aged rat discs and may be involved in IVDD. This study aimed to explore the mechanism of AOPPs-induced senescence in AF cells.MethodsThe pathological effects of AOPPs in vivo were investigated using a rat lumbar disc persistent degeneration model and a rat caudal disc puncture model. Rat primary AF cells were selected as in vitro models, and AOPPs were used as direct stimulation to observe their pathological effects. Setanaxb (NOX1/4 inhibitor), apocynin (NADPH oxidase inhibitor) and adenovirus (ADV) packed NADPH oxidase 4 (NOX4) specific shRNAs were used for pathway inhibition, respectively. Finally, adeno-associated viruses (AAVs) packed with NOX4-specific blocking sequences were used to inhibit the in vivo pathway.ResultsAOPPs accumulated in the rat lumbar and caudal degenerative discs. Intra-discal loading of AOPPs up-regulated the expression of NOX4, p53, p21, p16, IL-1β, and TNF-α, ultimately accelerating IVDD. Exposure of AOPPs to AF primary cells up-regulated NOX4 expression, induced phosphorylation of mitogen-activated protein kinases (MAPK), triggered senescence and increased IL-1β and TNF-α. Apocynin, setanaxib, and ADV pre-cultured AF cells abrogated AOPPs-induced senescence. AAV-mediated inhibition of NOX4 expression in vivo reduced the expression of p53, p21, p16, IL-1β and TNF-α in vivo and delayed IVDD.ConclusionsAOPPs induced AF cell senescence through a NOX4-dependent and MAPK-mediated pathway.

【 授权许可】

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