Journal
PEERJ
Volume 10, Issue -, Pages -Publisher
PEERJ INC
DOI: 10.7717/peerj.13826
Keywords
Senescence; Intervertebral disc degeneration; Advanced oxidized protein products; Inflammation associated with senescence
Categories
Funding
- National Natural Science Foundation of China [81772395]
- Medical Science and Technology Research Foundation of Guangdong Province [A2018256]
- Director Foundation of NanFang Hospital [2017Z015, 2019Z008]
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This study found that AOPPs induce senescence in AF cells through a NOX4-dependent and MAPK-mediated pathway, thereby accelerating IVDD.
Background. Intervertebral 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. Methods. The 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. Results. AOPPs accumulated in the rat lumbar and caudal degenerative discs. Intradiscal loading of AOPPs up-regulated the expression of NOX4, p53, p21, p16, IL-1 beta, and TNF-alpha, ultimately accelerating IVDD. Exposure of AOPPs to AF primary cells upregulated NOX4 expression, induced phosphorylation of mitogen-activated protein kinases (MAPK), triggered senescence and increased IL-1 beta and TNF-alpha. 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-1 beta and TNF-alpha in vivo and delayed IVDD. Conclusions. AOPPs induced AF cell senescence through a NOX4-dependent and MAPK-mediated pathway.
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