COL6A2 as a key regulator of extracellular matrix remodeling and nucleus pulposus cell migration in intervertebral disc degeneration

Abstract Clinical consensus holds that intervertebral disc degeneration (IVDD) is the most important etiology of discogenic pain. The essence of IVDD is the disruption of extracellular matrix (ECM) homeostasis. COL6A2 is an ECM structural protein, but its role in IVDD is not understood. We analyzed two GEO datasets (GSE70362 and GSE124272) for differential gene expression. We intersected the results with ECM metabolism-related genes from PathCards and obtained 39 ECM-related genes. GO and KEGG enrichment, PPI network construction, and CytoHubba were used to identify hub genes. COL6A2 expression was measured by RT-qPCR in clinical NP tissues. The needle-puncture model in mice was constructed. COL6A2 was knocked down in NP cells with lentivirus-delivered shRNA. COL6A2 emerged as the predominant hub gene. COL6A2 was significantly upregulated in degenerated NP tissues. Knockdown of COL6A2 reduced ADAMTS8, Aggrecan, LAMC1, and ITGA9 expression, suppressed phosphorylation of PI3K, FAK, Akt, and ERK1/2, and impaired cell migration and proliferation. LY294002 treatment phenocopied these ECM defects, confirming that COL6A2 regulates ECM homeostasis via the PI3K-Akt signaling pathway. These findings demonstrate that COL6A2 functions as an upstream coordinator of ECM homeostasis, orchestrating ECM remodeling and NP cell migration, and that its dysregulation in IVDD may actively drive the degenerative cascade.