SYSTEMATIC REVIEW article
Front. Med.
Sec. Pathology
MAPPING THE DEGENERATING INTERVERTEBRAL DISC: A SYSTEMATIC REVIEW OF HISTOLOGICAL EVIDENCE
Francesca Veronesi 1
Francesca Salamanna 1
Giuseppe Tedesco 2
Alberto Ruffilli 2
Francesco Rosa 1
Cesare Faldini 2
Gianluca Giavaresi 2
1. Unit of Surgical Sciences and Technologies, Rizzoli Orthopedic Institute (IRCCS), Bologna, Italy
2. IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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Abstract
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. Conclusions: 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.
Summary
Keywords
Histological changes, Immunohistochemical changes, Intervertebral Disc Degeneration, molecular data, Systematic review
Received
25 November 2025
Accepted
11 February 2026
Copyright
© 2026 Veronesi, Salamanna, Tedesco, Ruffilli, Rosa, Faldini and Giavaresi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Francesca Salamanna
Disclaimer
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