SIRT3 mitigates intervertebral disc degeneration by delaying oxidative stress‐induced senescence of nucleus pulposus cells. Issue 9 (9th February 2021)

• Record Type: Journal Article
• Authors: Lin, Jiayi; Du, Jiacheng; Wu, Xiexing; Xu, Congxin; Liu, Jiangtao; Jiang, Luyong; Cheng, Xiaoqiang; Ge, Gaoran; Chen, Liang; Pang, Qingjiang; Geng, Dechun; Mao, Haiqing
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 9(2021)
• Page Start: 6441
• Page End: 6456
• Publication Date: 2021-02-09
• Subjects: AMPK/PGC‐1α pathway -- cellular senescence -- intervertebral disc degeneration -- oxidative stress -- SIRT3; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30319
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Senescence of nucleus pulposus (NP) cells (NPC) is a major cause of intervertebral disc degeneration (IVDD), so delay NPC senescence may be beneficial for mitigating IVDD. We studied the effect and mechanism of silent information regulator 2 homolog 3 (SIRT3) on NPC senescence in vivo and in vitro. First, we observed SIRT3 expression in normal and degenerated NPC with immunohistochemical and immunofluorescence staining. Second, using SIRT3 lentivirus transfection, reactive oxygen species probe, senescence‐associated β‐galactosidase staining, polymerase chain reaction, and western blot to observe the oxidative stress, senescence, and degeneration degree among groups. Subsequently, pretreatment with adenosine monophosphate‐activated protein kinase (AMPK) agonists and inhibitors, observing oxidative stress, senescence, and degeneration degree among groups. Finally, the IVDD model was constructed and divided into Ctrl, Vehicle, LV‐shSIRT3, and LV‐SIRT3 groups. X‐ray and magnetic resonance imaging scans were performed on rat's tails after 1 week; hematoxylin and eosin and safranin‐O staining were used to evaluate the degree of IVDD; immunofluorescence staining was used to observe SIRT3 expression; immunohistochemical staining was used to observe oxidative stress, senescence, and degeneration degree of NP. We found that SIRT3 expression is reduced in degenerated NP tissues but increased in H2 O2 ‐induced NPC. Moreover, SIRT3 upregulation decreased oxidative stress, delayed senescence, and degeneration of NPC. In addition, activation of the AMPK/PGC‐1α pathway can partially mitigate the NPC oxidative stress, senescence, and degeneration caused by SIRT3 knockdown. The study in vivo revealed that local SIRT3 overexpression can significantly reduce oxidative stress and ECM degradation of NPC, delay NPC senescence, thereby mitigating IVDD. In summary, SIRT3 mediated by the AMPK/PGC‐1α pathway mitigates IVDD by delaying oxidative stress‐induced NPC senescence. Abstract : Schematic of the antisenescence effect of silent information regulator 2 homolog 3 (SIRT3) on oxidative stress‐induced nucleus pulposus cell (NPC). Activated AMPK (p‐AMPK) activates peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1a), which enters the nucleus to promote SIRT3 gene expression. After translation, SIRT3 transports to mitochondria to deacetylate Ac‐SOD2, thereby increasing superoxide dismutase 2 (SOD2) activity. And then SOD2 scavenges reactive oxygen species (ROS) induced by oxidative stress in NPC, thereby delaying the expression of p16INK4a, senescence‐associated β‐galactosidase (SA‐β‐Gal), and senescence‐associated secretory phenotype (SASP) in NPC so as to mitigate intervertebral disc degeneration (IVDD).