Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi-Axial Perspective of Mechanical, Immune, and Metabolic Pathways

IF 3.4 3区 医学 Q1 ORTHOPEDICS
JOR Spine Pub Date : 2025-07-02 DOI:10.1002/jsp2.70089
Yunbo Yang, Haoming Li, Junhui Zuo, Fei Lei
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Abstract

Background

The senescence of nucleus pulposus cells (NPCs) at the heart of the pathogenesis of intervertebral disc degeneration (IVDD), which causes low back pain. Abnormal mechanical stress causes intracellular Ca2+ overload by activating the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) channel.

Aims

This creates a positive feedback loop of oxidative-inflammatory damage by inducing endoplasmic reticulum stress and mitochondrial reactive oxygen species (ROS) bursts, as well as directly activating the NLRP3 inflammasome/NF-кB axis to promote the release of pro-inflammatory factors like IL-1β.

Results

Energy metabolism collapsed as a result of mechanistic cause that caused excessive activation of mitophagy via the ROS-PINK1/Parkin pathway, and SIRT1 functional suppression further compromised mitochondrial quality control. The inflammatory nucleus pulposus (NP) brought on by mechanical stimulation caused macrophages to polarize toward the M1 type, and the p38MAPK pathway was activated by the TNF-α/IL-1β released, which in turn increased senescence markers like p16/p21. Notably, ROS both triggers mitophagy and activates the p53 pathway. On the one hand, oxidative damage-induced ATM/ATR kinase activation leads to p53 phosphorylation, which triggers p21-mediated cell-cycle block. On the other hand, p53 exacerbates mitochondrial dysfunction by inhibiting SIRT1 expression, creating a triangular amplification loop of p53-ROS-mitophagy. Furthermore, p53 stimulates apoptosis by altering the Bax/Bcl-2 balance and works in concert with inflammatory substances secreted by M1-type macrophages to cause the development of senescence-associated secretory phenotype (SASP).

Conclusion

This interaction network reveals the dynamic coupling of mechano-immune-metabolic pathways in the course of IVDD, providing a theoretical basis for the development of multi-targeted intervention strategies, such as PIEZO1 inhibitors combined with M2-type macrophage polarization modulation, which are expected to delay disease progression by blocking key nodes.

Abstract Image

椎间盘退变中驱动髓核细胞衰老的机制相互作用:机械、免疫和代谢途径的多轴视角
髓核细胞(NPCs)的衰老是导致腰痛的椎间盘退变(IVDD)发病机制的核心。异常机械应力通过激活压电型机械敏感离子通道组分1 (PIEZO1)通道导致细胞内Ca2+过载。通过诱导内质网应激和线粒体活性氧(ROS)爆发,以及直接激活NLRP3炎性小体/NF-кB轴,促进IL-1β等促炎因子的释放,形成氧化炎症损伤的正反馈循环。结果能量代谢崩溃是通过ROS-PINK1/Parkin通路导致线粒体自噬过度激活的机制原因,SIRT1功能抑制进一步损害线粒体质量控制。机械刺激引起的炎性髓核(NP)使巨噬细胞向M1型极化,释放的TNF-α/IL-1β激活了p38MAPK通路,从而增加了p16/p21等衰老标志物。值得注意的是,ROS既触发有丝分裂又激活p53通路。一方面,氧化损伤诱导的ATM/ATR激酶激活导致p53磷酸化,从而触发p21介导的细胞周期阻滞。另一方面,p53通过抑制SIRT1表达加剧线粒体功能障碍,形成p53- ros -mitophagy的三角形扩增环。此外,p53通过改变Bax/Bcl-2平衡刺激细胞凋亡,并与m1型巨噬细胞分泌的炎症物质协同作用,导致衰老相关分泌表型(SASP)的发展。结论该相互作用网络揭示了IVDD过程中机械-免疫-代谢途径的动态耦合,为开发多靶向干预策略提供了理论基础,如PIEZO1抑制剂联合m2型巨噬细胞极化调节,有望通过阻断关键节点来延缓疾病进展。
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来源期刊
JOR Spine
JOR Spine ORTHOPEDICS-
CiteScore
6.40
自引率
18.90%
发文量
42
审稿时长
10 weeks
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