Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 236, Issue 9, Pages 6441-6456Publisher
WILEY
DOI: 10.1002/jcp.30319
Keywords
AMPK/PGC-1 alpha pathway; cellular senescence; intervertebral disc degeneration; oxidative stress; SIRT3
Categories
Funding
- National Nature Science Foundation of China [81972104, 82072425, 82030068, 91849114, 81873990, 81873991, 81672238, 81372018]
- Jiangsu Provincial Medical Youth Talent [QNRC2016751]
- Natural Science Foundation of Jiangsu Province [BK20180001]
- National Key RD Program [2016YFC1101505]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Special Project of Diagnosis and Treatment for Clinical Diseases of Suzhou [LCZX202003]
- application of key technology research program of Suzhou City [SS201858]
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The study showed that SIRT3 can delay NPC senescence, reducing oxidative stress and mitigating intervertebral disc degeneration. The activation of the AMPK/PGC-1 alpha pathway partially regulates the effects of SIRT3, indicating a potential therapeutic target for IVDD.
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 beta-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 H2O2-induced NPC. Moreover, SIRT3 upregulation decreased oxidative stress, delayed senescence, and degeneration of NPC. In addition, activation of the AMPK/PGC-1 alpha 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-1 alpha pathway mitigates IVDD by delaying oxidative stress-induced NPC senescence.
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