Mapping the degenerating intervertebral disc: a systematic review of histological evidence

Introduction Intervertebral disc degeneration (IDD) is a major cause of low back pain and disability. While MRI remains the standard diagnostic tool, it provides limited insight into the cellular and molecular changes underlying IDD. Histological analysis offers a complementary approach to characterizing the degenerative process in human intervertebral discs (IVDs). This systematic review aims to provide a comprehensive analysis of histological and immunohistochemical changes across the IVD, nucleus pulposus (NP), and cartilage endplate (CEP) in degenerated human discs. Methods A literature search was conducted in PubMed, Scopus, and Web of Science for studies published between 2015 and 2025. A total of 45 human studies were included. Histological features, protein expression profiles, and grading systems were analyzed. Differentially expressed proteins were mapped into protein–protein interaction (PPI) networks using the STRING database. Results Common histopathological features included ECM disorganization, proteoglycan depletion, fibrosis, neovascularization, and cell clustering. Molecular data revealed upregulation of catabolic enzymes, inflammatory cytokines, apoptotic mediators, and angiogenic factors. Conversely, regenerative and protective markers were significantly downregulated. PPI analysis revealed region-specific pathways: ECM remodeling and BMP/VEGF signaling in the IVD, inflammation and mechanotransduction in the NP, and ossification and prostaglandin signaling in the CEP. Conclusion Histology reveals spatially distinct yet converging degenerative pathways across IVD regions. These findings identify potential biomarkers and therapeutic targets, supporting histological analysis as an essential complement to imaging for accurate IDD characterization.