Abstract
The transcriptional repressor Bmi‐1 is involved in cell‐cycle regulation and cell senescence, the deficiency of which has been shown to cause oxidative stress. This study investigated whether Bmi‐1 deficiency plays a role in promoting disc degeneration and the effect of treatment with antioxidant N‐acetylcysteine (NAC) on intervertebral disc degeneration. Bmi‐1−/− mice were treated with the antioxidant NAC, supplied in drinking water (Bmi‐1−/−+NAC). For in vitro experiments, mouse intervertebral discs were cultured under low oxygen tension and serum‐limiting conditions in the presence of tumour necrosis factor α and interleukin 1β in order to mimic degenerative insult. Disc metabolism parameters in these in vitro and in vivo studies were evaluated by histopathological, immunohistochemical and molecular methods. Bmi‐1−/− mice showed lower collagen Ⅱ and aggrecan levels and higher collagen Ⅹ levels than wild‐type and Bmi‐1−/−+NAC mice. Bmi‐1−/− mice showed significantly lower superoxide dismutase (SOD)‐1, SOD‐2, glutathione peroxidase (GPX)‐1 and GPX‐3 levels than their wild‐type littermates and Bmi‐1−/−+ NAC mice. Relative to Bmi‐1−/− mice, the control and Bmi‐1−/−+NAC mice showed significantly lower p16, p21, and p53 levels. These results demonstrate that Bmi‐1 plays an important role in attenuating intervertebral disc degeneration in mice by inhibiting oxidative stress and cell apoptosis.
Highlights
We explored the role of Bmi-1 on mouse intervertebral disc degeneration using Bmi-1 gene knockout mice in vivo and organ culture in vitro and investigated the effect of N-acetylcysteine (NAC) treatment on intervertebral disc degeneration
Oxidative stress contributes to the cartilage endplate degeneration and nucleus pulposus (NP) cells apoptosis.[20,21,22]
We have investigated the role and mechanism of action of Bmi-1 in Intervertebral disc degeneration (IDD) and found Bmi-1 gene knock out caused IDD in the mutant mice compared with the WT, associating with the redox disbalance both in vivo and in vitro
Summary
Intervertebral disc degeneration (IDD) is associated with diverse aetiologies such as mechanical stress, injury, ageing, obesity and genetic factors.[1,2] Cellular senescence has been demonstrated to be a natural part of the disc ageing process. Loss of water content and ECM breakdown are usually found in IDD,[5] and IDD is characterized by an increased expression of proinflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor α (TNF-α).[6,7] The condition is associated with ROS production and oxidative stress.[8,9] pathobiology for IDD is unclear. Bmi-1−/− mice could be generally rescued by the treatment with the antioxidant N-acetylcysteine (NAC), including a prolonged lifespan and an increased body size.[11,12] it is unclear whether Bmi-1 deficiency could lead to IDD. This study has elucidated the association between Bmi-1 and oxidative stress in IDD, which will provide a foundation for developing new drugs for attenuating IDD
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