Frontiers in immunology · 2026
Deciphering the regulatory mechanism and therapeutic potential of ECM degradation in intervertebral disc degeneration via multi-omics integration.
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Feng Lei, Zhong Wei, Liu Wenhua, Guo Xiang, Wu Leilei
Аннотация
BACKGROUND: Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, characterized not only by extracellular matrix (ECM) degradation but also by a chronic low-grade inflammatory response. The crosstalk between immune microenvironment dysregulation and protease-driven ECM breakdown remains poorly understood, hindering the development of targeted therapies.
METHODS: We integrated multiple transcriptomic datasets to map the landscape of ECM-degrading proteases in IVDD. Machine learning algorithms (LASSO, Random Forest, SVM) were employed to identify key regulatory genes. Their association with immune cell infiltration and inflammatory pathways was investigated. A diagnostic ridge regression model was constructed, and molecular docking was performed to screen for potential therapeutics. The top candidate, pravastatin sodium, was validated in vitro and in vivo for its effects on ECM preservation and inflammation modulation.
RESULTS: MMP3 and ADAMTS1 were identified as core genes driving ECM degradation, and their expression was strongly correlated with the abundance of pro-inflammatory immune cells and activation of inflammatory pathways. The model based on these genes effectively distinguished degenerated discs. Single-cell analysis revealed that high-degradation nucleus pulposus cells exhibited enhanced pro-inflammatory intercellular communication and metabolic reprogramming towards a pro-inflammatory state. Molecular docking confirmed high binding affinity of pravastatin sodium to MMP3 and ADAMTS1. Experimental validation demonstrated that pravastatin sodium alleviated IVDD by reducing ECM degradation, suppressing pro-inflammatory cytokine (e.g., IL-1β) expression, and inhibiting apoptosis.
CONCLUSION: Our study delineates a critical network linking ECM degradation to immune microenvironment activation in IVDD, with MMP3 and ADAMTS1 serving as central hubs. Pravastatin sodium emerges as a promising therapeutic agent capable of disrupting this pathogenic network, offering a novel immunomodulatory strategy for slowing disc degeneration.
METHODS: We integrated multiple transcriptomic datasets to map the landscape of ECM-degrading proteases in IVDD. Machine learning algorithms (LASSO, Random Forest, SVM) were employed to identify key regulatory genes. Their association with immune cell infiltration and inflammatory pathways was investigated. A diagnostic ridge regression model was constructed, and molecular docking was performed to screen for potential therapeutics. The top candidate, pravastatin sodium, was validated in vitro and in vivo for its effects on ECM preservation and inflammation modulation.
RESULTS: MMP3 and ADAMTS1 were identified as core genes driving ECM degradation, and their expression was strongly correlated with the abundance of pro-inflammatory immune cells and activation of inflammatory pathways. The model based on these genes effectively distinguished degenerated discs. Single-cell analysis revealed that high-degradation nucleus pulposus cells exhibited enhanced pro-inflammatory intercellular communication and metabolic reprogramming towards a pro-inflammatory state. Molecular docking confirmed high binding affinity of pravastatin sodium to MMP3 and ADAMTS1. Experimental validation demonstrated that pravastatin sodium alleviated IVDD by reducing ECM degradation, suppressing pro-inflammatory cytokine (e.g., IL-1β) expression, and inhibiting apoptosis.
CONCLUSION: Our study delineates a critical network linking ECM degradation to immune microenvironment activation in IVDD, with MMP3 and ADAMTS1 serving as central hubs. Pravastatin sodium emerges as a promising therapeutic agent capable of disrupting this pathogenic network, offering a novel immunomodulatory strategy for slowing disc degeneration.