Abstract
One of the causes of intervertebral disc degeneration (IVDD) is nucleus pulposus cell (NPC) death, possibly apoptosis. In this study, we explored the role of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated the potential working mechanism. Reactive oxygen species (ROS) assay kits and malondialdehyde (MDA) assay kits were used to assess oxidative stress. Western blot and TUNEL staining were used to examine apoptosis. After siRNA against Nrf2 or lentivirus against Sirt3 was transfected into NPCs, the mechanism of the effect of the Nrf2/Sirt3 pathway on NPCs was assessed. The interaction between t-BHQ and its potential interacting protein NRF2 was further investigated through protein docking analysis. ChIP examined the binding affinity between Nrf2 and Sirt3 promoter. In vivo experiments, X-ray, hematoxylin-eosin (HE) staining, Safranin O staining, and immunohistochemistry were used to evaluate IVDD grades. The results demonstrated that activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5. Furthermore, t-BHQ ameliorated IVDD development in a rat model. In conclusion, our findings indicate that the Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD.
Highlights
Low back pain is one of the most common causes of disability in developed countries, and the number of affected patients is increasing worldwide [1]
These results show that levels of nuclear respiratory factor 2 (Nrf2) are correlated with the severity of intervertebral disc degeneration (IVDD)
We found that t-BHQ reversed the loss in cell viability observed in response to tert-Butyl hydroperoxide solution (TBHP) stimulation in a dose-dependent manner
Summary
Low back pain is one of the most common causes of disability in developed countries, and the number of affected patients is increasing worldwide [1]. This disease exerts an enormous socioeconomic burden on societies, families, and individuals. Effective interventions are still hampered because the many causes of low back pain are not well understood. A strong relationship between low back pain and intervertebral disc degeneration has been documented [2,3,4]. The etiology of intervertebral disc degeneration is unclear, and most investigators agree with the current idea that it is “multifactorial” in nature. Reducing apoptotic cells is an effective method to delay IVDD
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