SIRT1 通过 ERK 信号通路促进人椎间盘细胞退变关键期自噬流来抑制细胞凋亡。
SIRT1 Inhibits Apoptosis by Promoting Autophagic Flux in Human Nucleus Pulposus Cells in the Key Stage of Degeneration via ERK Signal Pathway.
机构信息
Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Pathology, Chongqing Medical University, Chongqing 400010, China.
出版信息
Biomed Res Int. 2021 Feb 27;2021:8818713. doi: 10.1155/2021/8818713. eCollection 2021.
BACKGROUND
The application of biomolecular interventions in the early stage of intervertebral disc degeneration (IVDD) is considered an ideal method for the treatment of IVDD. However, the precise definition of the "early stage" of IVDD is unclear. Silent information regulation 2 homologue-1 (SIRT1) can protect human degenerative nucleus pulposus (NP) cells from apoptosis by activating autophagy. However, the mechanism of this effect is still unclear. This study tried to confirm the "early stage" of IVDD and the role of NP cell autophagy during IVDD as well as to determine the mechanism by which SIRT1 protects NP cells.
METHODS
The characteristics of the NP in various stages of degeneration were assessed to confirm the "early stage" of IVDD. Then, autophagy and apoptosis were detected in NP cells after SIRT1 upregulation/downregulation. Finally, LY294002 and PD98059 were used to inhibit the AKT/ERK pathway to determine the mechanism by which SIRT1 regulates autophagy in NP cells.
RESULTS
Our data showed that mildly degenerative (Pfirrmann grade III with normal height of intervertebral disc) NP cells may be the key target for biomolecular interventions in IVDD and that SIRT1 protects human mildly degenerative NP cells from apoptosis by activating autophagy via the ERK signalling pathway.
CONCLUSION
Our data showed that SIRT1 inhibits apoptosis by promoting the autophagic flux in NP cells via the ERK signalling pathway during the key stage of degeneration. These findings will assist in the development of novel therapeutic approaches for IVDD treatment.
背景
生物分子干预在椎间盘退变（IVDD）的早期阶段的应用被认为是治疗 IVDD 的理想方法。然而，IVDD 的“早期阶段”的精确定义尚不清楚。沉默信息调节因子 2 同源物 1（SIRT1）可以通过激活自噬来保护人退变的髓核（NP）细胞免于凋亡。然而，这种作用的机制尚不清楚。本研究试图确认 IVDD 的“早期阶段”以及 NP 细胞自噬在 IVDD 过程中的作用，并确定 SIRT1 保护 NP 细胞的机制。
方法
评估 NP 在退变各阶段的特征，以确认 IVDD 的“早期阶段”。然后，上调/下调 SIRT1 后检测 NP 细胞中的自噬和凋亡。最后，使用 LY294002 和 PD98059 抑制 AKT/ERK 通路，以确定 SIRT1 调节 NP 细胞自噬的机制。
结果
我们的数据表明，轻度退变（Pfirrmann 分级 III 伴椎间盘高度正常）的 NP 细胞可能是 IVDD 生物分子干预的关键靶点，SIRT1 通过 ERK 信号通路激活自噬来保护人轻度退变的 NP 细胞免于凋亡。
结论
我们的数据表明，SIRT1 通过 ERK 信号通路抑制 NP 细胞中的凋亡，促进自噬流。这些发现将有助于开发治疗 IVDD 的新治疗方法。
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