Apoptotic Pathway in Intervertebral Disc Degeneration: From Molecular Pathways to Clinical Interventions

Abstract

Apoptosis plays a crucial role in the progression of intervertebral disc degeneration (IVDD), a significant cause of chronic low back pain. This review explores disc cell apoptosis's cellular and molecular mechanisms, focusing on nucleus pulposus, annulus fibrosus, and cartilage endplates cells. Apoptotic pathways-intrinsic (mitochondrial), extrinsic (death receptor-mediated), ER stress-mediated, and autophagy-related-are activated by oxidative stress, inflammation, mechanical load, and metabolic disturbances like hyperglycemia. Diabetes exacerbates disc cell apoptosis through AGE-RAGE signaling and mitochondrial dysfunction. Inflammation further amplifies apoptotic cascades via cytokine signaling and ROS generation. The review also examines emerging therapeutic strategies, including antioxidants (e.g., MitoQ, resveratrol), anti-inflammatory agents (e.g., cytokine inhibitors), autophagy modulators (e.g., rapamycin, metformin), and stem cell and gene therapies. While promising preclinical results exist, challenges such as poor bioavailability and clinical translation remain. Enhanced understanding of apoptosis pathways informs future cellular preservation and matrix integrity treatments. Based on a comprehensive literature search from 2000 to 2025, this narrative review synthesizes current knowledge, identifies knowledge gaps, and discusses translational potential. Our findings support a paradigm shift toward mechanism-based therapies that address the root cause of IVDD rather than symptomatic relief alone.

Keywords: ER stress; apoptosis; autophagy; disc cells; hyperglycemia; inflammation; intervertebral disc degeneration; mitochondrial dysfunction.

Figure 1

Molecular pathways of apoptosis in intervertebral disc degeneration (IVDD). This diagram illustrates the converging apoptotic pathways in IVD cells, including NP, AF, and CEPs cells, under the influence of both local and systemic stressors. Local stressors such as hypoxia, nutrient deprivation, acidosis, mechanical overload, and avascularity directly activate oxidative stress and endoplasmic reticulum (ER) stress in disc cells. Systemic factors, including hyperglycemia and chronic inflammation, amplify these stress responses. Four primary apoptotic signaling cascades are depicted: Intrinsic (mitochondrial) pathway [3,4,5]: Triggered by oxidative stress, mitochondrial dysfunction, and DNA damage, leading to cytochrome c release, apoptosome formation, and caspa-se-9/3 activation. Extrinsic (death receptor-mediated) pathway [3,9,28,30]: Activated by inflammatory cytokines such as TNF-α and Fas ligand (FasL), engaging receptors (e.g., TNFR1 and Fas initiate caspase-8 activation and interact with the intrinsic pathway through Bid cleavage. ER stress pathway [7,47]: Prolonged ER stress upregulates CHOP, which downregulates Bcl-2 and promotes mitochondrial-mediated apoptosis; this can activate caspase-12 and link to mitochondrial and autophagic pathways. Autophagy-apoptosis crosstalk [10,13,20,48,49]: Autophagy protects against apoptosis by degrading damaged organelles. However, dysregulated autophagy triggers apoptosis under chronic stress through Beclin-1 cleavage and p62 accumulation. All pathways converge on caspase activation, ultimately resulting in apoptosis and degradation of the ECM, which drives structural failure and disc degeneration. Arrows in the figure highlight the feedback and crosstalk between pathways.

Figure 2

Therapeutic strategies to mitigate disc cell apoptosis in intervertebral disc degeneration (IVDD). The figure summarizes current therapeutic approaches aimed at reducing apoptosis of disc cells, including NP and AF cells. These strategies are categorized into five main domains: (1) antioxidants and mitochondrial-targeted agents to reduce oxidative stress and preserve mitochondrial function [79,80]; (2) anti-inflammatory therapeutics targeting proinflammatory cytokines and signaling pathways [76,77,78,79,81]; (3) autophagy modulators to enhance cytoprotective autophagic flux [79,80,82]; (4) inhibitors of apoptotic signaling pathways such as caspases, Bcl-2 family proteins, and ER stress mediators [76,77]; and (5) regenerative and cell-based therapies including mesenchymal stem cell transplantation [78,83,84,85], exosome-based delivery of antiapoptotic microRNAs [86,87,88,89,90], and gene therapy approaches [90,91]. These interventions act at different levels of the apoptotic cascade and promise to halt or reverse disc degeneration.