Abstract
Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 μM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.
Highlights
Low-back pain pervasively affects up to 80% of adults at a certain period during their life time[1]
To determine whether Sirtuin 3 (SIRT3) expression was correlated with intervertebral disc degeneration (IVDD), human nucleus pulposus (NP) tissues of patients from different degenerative degrees were harvested to measure the SIRT3 level by Western blotting
Because the expression of SIRT3 in degenerative human nucleus pulposus cells (NPCs) was not consistent with that in rat NPCs treated with TBHP, we knocked down and overexpressed SIRT3 to determine whether SIRT3 acted as a protective mediator against oxidative stress in NPCs
Summary
Low-back pain pervasively affects up to 80% of adults at a certain period during their life time[1]. Intervertebral disc degeneration (IVDD) is considered to be the main cause of low-back pain[2]. Nucleus pulposus cells (NPCs) exhibit dramatic molecular changes in extracellular matrix (ECM) metabolism, which depends on the quality of NPCs3. Oxidative stress is common in degenerative IVDs resulting from age-related diseases, such as diabetes[4]. It has been reported that oxidative stress may induce disc cell apoptosis, senescence, and abnormal matrix metabolism[5]. Studies have demonstrated that mitochondrial dysfunction is involved in diverse degenerative diseases, including IVDD6–8, and dysfunctional mitochondria are the major source of reactive oxygen species (ROS) in cells. The maintenance of mitochondrial homeostasis is considered a therapeutic target for these diseases
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