{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T03:22:31Z","timestamp":1781839351732,"version":"3.54.5"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013protein interaction (PPI) networks using the STRING database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1753988","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:44:47Z","timestamp":1772023487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mapping the degenerating intervertebral disc: a systematic review of histological evidence"],"prefix":"10.3389","volume":"13","author":[{"given":"Francesca","family":"Veronesi","sequence":"first","affiliation":[{"name":"Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Salamanna","sequence":"additional","affiliation":[{"name":"Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ruffilli","sequence":"additional","affiliation":[{"name":"1st Orthopaedic and Traumatologic Department, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]},{"name":"Department of Biomedical and Neuromotor Science-DIBINEM, University of Bologna","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Rosa","sequence":"additional","affiliation":[{"name":"Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Faldini","sequence":"additional","affiliation":[{"name":"1st Orthopaedic and Traumatologic Department, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]},{"name":"Department of Biomedical and Neuromotor Science-DIBINEM, University of Bologna","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Giavaresi","sequence":"additional","affiliation":[{"name":"Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0140-6736(21)00733-9","article-title":"Low back pain","volume":"398","author":"Knezevic","year":"2021","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1136\/ard.2010.137836","article-title":"Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK twin spine study","volume":"70","author":"Livshits","year":"2011","journal-title":"Ann Rheum Dis"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1016\/S2665-9913(23)00098-X.","article-title":"Global, regional, and national burden of low back pain 1990\u20132020 its attributable risk factors and projections to 2050 a systematic analysis of the global burden of disease study 2021","volume":"5","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1080\/15548627.2020.1822097","article-title":"Mitophagy in degenerative joint diseases","volume":"17","author":"Sun","year":"2021","journal-title":"Autophagy"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.freeradbiomed.2022.08.018","article-title":"Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes","volume":"190","author":"Wang","year":"2022","journal-title":"Free Radic Biol Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1111\/j.1533-2500.2007.00171.x","article-title":"Intervertebral disc: anatomy-physiology-pathophysiology-treatment","volume":"8","author":"Raj","year":"2008","journal-title":"Pain Pract"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.3390\/ijms21062135","article-title":"Intervertebral disc diseases part 2: a review of the current diagnostic and treatment strategies for intervertebral disc disease","volume":"21","author":"Wu","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.ocl.2011.07.012","article-title":"Structure and biology of the intervertebral disk in health and disease","volume":"42","author":"Chan","year":"2011","journal-title":"Orthop Clin North Am"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"6915","DOI":"10.3390\/ijms23136915","article-title":"Importance of matrix cues on intervertebral disc development, degeneration, and regeneration","volume":"23","author":"Kibble","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"100036","DOI":"10.1016\/j.mbplus.2020.100036","article-title":"Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration","author":"Ohnishi","year":"2020","journal-title":"Matrix Biol Plus"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.ebiom.2019.10.006","article-title":"Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9","volume":"48","author":"Jiang","year":"2019","journal-title":"EBioMedicine"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/s41584-022-00783-7","article-title":"Mechanisms and clinical implications of intervertebral disc calcification","volume":"18","author":"Zehra","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"420","DOI":"10.3390\/diagnostics12020420","article-title":"Novel magnetic resonance imaging tools for the diagnosis of degenerative disc disease: a narrative review","volume":"12","author":"Mallio","year":"2022","journal-title":"Diagnostics (Basel)"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1097\/00007632-200109010-00011","article-title":"Magnetic resonance classification of lumbar intervertebral disc degeneration","volume":"26","author":"Pfirrmann","year":"2001","journal-title":"Spine"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1148\/radiology.166.1.3336678","article-title":"Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging","volume":"166","author":"Modic","year":"1988","journal-title":"Radiology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e0139283","DOI":"10.1371\/journal.pone.0139283","article-title":"Structural and ultrastructural analysis of the cervical discs of young and elderly humans","volume":"10","author":"de Vasconcellos Fontes","year":"2015","journal-title":"PLoS One"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1186\/1756-0500-4-497","article-title":"Histological analysis of surgical lumbar intervertebral disc tissue provides evidence for an association between disc degeneration and increased body mass index","volume":"4","author":"Weiler","year":"2011","journal-title":"BMC Res Notes"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"529","DOI":"10.7326\/0003-4819-155-8-201110180-00009","article-title":"QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies","volume":"155","author":"Whiting","year":"2011","journal-title":"Ann Intern Med"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1016\/j.spinee.2021.03.002","article-title":"Bone morphogenic protein-2 signaling in human disc degeneration and correlation to the Pfirrmann MRI grading system","volume":"21","author":"Hollenberg","year":"2021","journal-title":"Spine J"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/s41420-019-0233-z","article-title":"Physical disruption of intervertebral disc promotes cell clustering and a degenerative phenotype","volume":"5","author":"Lama","year":"2019","journal-title":"Cell Death Dis"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"994307","DOI":"10.3389\/fendo.2022.994307","article-title":"Necroptosis of nucleus pulposus cells involved in intervertebral disc degeneration through MyD88 signaling","volume":"13","author":"Fan","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s00586-020-06592-4","article-title":"Terminal complement complex formation is associated with intervertebral disc degeneration","volume":"30","author":"Teixeira","year":"2021","journal-title":"Eur Spine J"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1016\/j.joca.2025.02.783","article-title":"Beta-defensin 1 knockdown ameliorates the characteristics of intervertebral disc degeneration by altering nucleus pulposus and annulus fibrosus cell phenotypes via suppression of the extracellular signal-regulated kinase signaling pathway","volume":"33","author":"Wei","year":"2025","journal-title":"Osteoarthr Cartil"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"eAO4637","DOI":"10.31744\/einstein_journal\/2019AO4637","article-title":"Inflammatory biomarkers in sera of patients with intervertebral disc degeneration","volume":"17","author":"Rodrigues","year":"2019","journal-title":"Einstein (S\u00e3o Paulo)"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1002\/jor.23583","article-title":"Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration","volume":"35","author":"Alvarez-Garcia","year":"2017","journal-title":"J Orthop Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.14670\/HH-18-107","article-title":"Role of heparan sulfate 6-0 endosulfatases in intervertebral disc homeostasis","volume":"34","author":"Otsuki","year":"2019","journal-title":"Histol Histopathol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e1215","DOI":"10.1002\/jsp2.1215","article-title":"Neoepitope fragments as biomarkers for different phenotypes of intervertebral disc degeneration","volume":"5","author":"Cui","year":"2022","journal-title":"JOR Spine"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e686","DOI":"10.1016\/j.wneu.2018.07.243","article-title":"Cervical intervertebral disc degeneration contributes to dizziness: a clinical and immunohistochemical study","volume":"119","author":"Yang","year":"2018","journal-title":"World Neurosurg"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"7829","DOI":"10.1038\/s41598-019-44373-2","article-title":"Vitamin D receptor gene polymorphisms and plasma levels are associated with lumbar disc degeneration","volume":"9","author":"Yang","year":"2019","journal-title":"Sci Rep"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"E1053","DOI":"10.1097\/brs.0000000000003059","article-title":"Paraoxonase 1 was negatively associated with intervertebral disc degeneration","volume":"44","author":"Chen","year":"2019","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"071006","DOI":"10.1115\/1.4056871","article-title":"Diffusivity of human cartilage endplates in healthy and degenerated intervertebral disks","volume":"145","author":"Ren","year":"2023","journal-title":"J Biomech Eng"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"255","DOI":"10.3233\/BMR-181488","article-title":"Expression and role of sphingosine 1-phosphate receptors in intervertebral disc degeneration","volume":"33","author":"Yang","year":"2020","journal-title":"J Back Musculoskelet Rehabil"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.joca.2018.04.002","article-title":"Wnt5a suppresses inflammation-driven intervertebral disc degeneration via a TNF-\u03b1\/NF-\u03baB-Wnt5a negative-feedback loop","volume":"26","author":"Li","year":"2018","journal-title":"Osteoarthr Cartil"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"382","DOI":"10.5115\/acb.23.067","article-title":"Cell clusters in intervertebral disc degeneration: an attempted repair mechanism aborted via apoptosis","volume":"56","author":"Lama","year":"2023","journal-title":"Anat Cell Biol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"18338","DOI":"10.18632\/oncotarget.4274","article-title":"Class 3 semaphorins expression and association with innervation and angiogenesis within the degenerate human intervertebral disc","volume":"6","author":"Binch","year":"2015","journal-title":"Oncotarget"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.spinee.2017.09.018","article-title":"Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration","volume":"18","author":"Nakazawa","year":"2018","journal-title":"Spine J"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"274","DOI":"10.5137\/1019-5149.JTN.12762-14.0","article-title":"Evaluation of the association between matrix metalloproteinase 11 and intervertebral disc disease","volume":"26","author":"Aras","year":"2016","journal-title":"Turk Neurosurg"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s13075-025-03489-9","article-title":"Proteomic profiling of human plasma and intervertebral disc tissue reveals matrisomal, but not plasma, biomarkers of disc degeneration","volume":"27","author":"Dube","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"8884922","DOI":"10.1155\/2021\/8884922","article-title":"Mechanosensitive ion channel Piezo1 activated by matrix stiffness regulates oxidative stress-induced senescence and apoptosis in human intervertebral disc degeneration","volume":"2021","author":"Wang","year":"2021","journal-title":"Oxidative Med Cell Longev"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1792412","DOI":"10.1155\/2022\/1792412","article-title":"Depleted long noncoding RNA GAS5 relieves intervertebral disc degeneration via microRNA-17-3p\/Ang-2","volume":"2022","author":"Yu","year":"2022","journal-title":"Oxidative Med Cell Longev"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12974-025-03335-4","article-title":"Therapeutic potential of targeting the IRF2\/POSTN\/Notch1 axis in nucleus pulposus cells for intervertebral disc degeneration","volume":"22","author":"Zhu","year":"2025","journal-title":"J Neuroinflammation"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"783","DOI":"10.3892\/mmr.2016.5341","article-title":"SDF-1\/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF-\u03baB pathway","volume":"14","author":"Liu","year":"2016","journal-title":"Mol Med Rep"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e70029","DOI":"10.1002\/jsp2.70029","article-title":"CD24 positive nucleus pulposus cells in adult human intervertebral discs maintain a more notochordal phenotype than GD2 positive cells","volume":"7","author":"Ionescu","year":"2024","journal-title":"JOR Spine"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"E757","DOI":"10.1097\/BRS.0000000000001954","article-title":"Role of Sirt1 plays in nucleus pulposus cells and intervertebral disc degeneration","volume":"42","author":"Guo","year":"2017","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"E54","DOI":"10.1097\/BRS.0000000000004486","article-title":"miR-4478 accelerates nucleus pulposus cells apoptosis induced by oxidative stress by targeting MTH1","volume":"48","author":"Zhang","year":"2023","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1133615","DOI":"10.3389\/fgene.2023.1133615","article-title":"Identifification and validation of ferroptosis signatures and immune infifiltration characteristics associated with intervertebral disc degeneration","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Genet"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"9684062","DOI":"10.1155\/2022\/9684062","article-title":"Irisin ameliorates intervertebral disc degeneration by activating LATS\/YAP\/CTGF signaling","volume":"2022","author":"Chen","year":"2022","journal-title":"Oxidative Med Cell Longev"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"4730","DOI":"10.3892\/mmr.2017.7178","article-title":"Collagen type II is downregulated in the degenerative nucleus pulposus and contributes to the degeneration and apoptosis of human nucleus pulposus cells","volume":"16","author":"Lian","year":"2017","journal-title":"Mol Med Rep"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"5737","DOI":"10.1111\/jcmm.14488","article-title":"Angiopoietin-like protein 8 expression and association with extracellular matrix metabolism and inflammation during intervertebral disc degeneration","volume":"23","author":"Liao","year":"2019","journal-title":"J Cell Mol Med"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"112202","DOI":"10.1016\/j.intimp.2024.112202","article-title":"MINK1 deficiency stimulates nucleus pulposus cell pyroptosis and exacerbates intervertebral disc degeneration","volume":"134","author":"Zhan","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/s41419-019-1701-3","article-title":"Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1\/Nrf2\/p62 feedback loop to protect intervertebral disc from degeneration","volume":"10","author":"Tang","year":"2019","journal-title":"Cell Death Dis"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"11945","DOI":"10.18632\/oncotarget.3631","article-title":"Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: novel HIF-1-mediated regulation of aquaporins in NP cells","volume":"6","author":"Johnson","year":"2015","journal-title":"Oncotarget"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.jot.2025.01.006","article-title":"Targeting Piezo1 channel to alleviate intervertebral disc degeneration","volume":"51","author":"Li","year":"2025","journal-title":"J Orthop Translat"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.3892\/ijmm.2018.3576","article-title":"Angiopoietin-2 promotes extracellular matrix degradation in human degenerative nucleus pulposus cells","volume":"41","author":"Wang","year":"2018","journal-title":"Int J Mol Med"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jot.2024.12.009","article-title":"LRP1 mitigates intervertebral disc degeneration by inhibiting endoplasmic reticulum stress through stabilizing the PPAR\u03b3","volume":"50","author":"Yao","year":"2025","journal-title":"J Orthop Translat"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"27868","DOI":"10.18632\/oncotarget.15838","article-title":"MicroRNA-494 promotes apoptosis and extracellular matrix degradation in degenerative human nucleus pulposus cells","volume":"8","author":"Kang","year":"2017","journal-title":"Oncotarget"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.joca.2025.02.771","article-title":"EZH2 inhibits senescence-associated inflammation and attenuates intervertebral disc degeneration by regulating the cGAS\/STING pathway via H3K27me3","volume":"33","author":"Zheng","year":"2025","journal-title":"Osteoarthr Cartil"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1002\/cbin.11851","article-title":"YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension","volume":"46","author":"Ding","year":"2022","journal-title":"Cell Biol Int"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1111\/joa.13321","article-title":"Damage to the human lumbar cartilage endplate and its clinical implications","volume":"238","author":"Huang","year":"2021","journal-title":"J Anat"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.joca.2022.10.008","article-title":"Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598","volume":"31","author":"Huang","year":"2023","journal-title":"Osteoarthr Cartil"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.spinee.2024.04.003","article-title":"Association between vertebral endplate defects and patient-reported symptoms: an immunohistochemical study investigating the COX-2\/PGE-2\/EP-4 axis","volume":"24","author":"Chen","year":"2024","journal-title":"Spine J"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s10020-024-00887-8","article-title":"Dysregulated lipid metabolism and intervertebral disc degeneration: the important role of ox-LDL\/LOX-1 in endplate chondrocyte senescence and calcification","volume":"30","author":"Bing","year":"2024","journal-title":"Mol Med"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s00586-004-0759-4","article-title":"Correlation of radiographic and MRI parameters to morphological and biochemical assessment of intervertebral disc degeneration","volume":"14","author":"Benneker","year":"2005","journal-title":"Eur Spine J"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1097\/00007632-198704000-00016","article-title":"Magnetic resonance imaging in the diagnosis of disc degeneration: correlation with discography","volume":"12","author":"Schneiderman","year":"1987","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1136\/mp.55.2.91","article-title":"Expression of chondrocyte markers by cells of normal and degenerate intervertebral discs","volume":"55","author":"Sive","year":"2002","journal-title":"Mol Pathol"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1016\/j.joca.2013.10.001","article-title":"A validated new histological classification for intervertebral disc degeneration","volume":"21","author":"Rutges","year":"2013","journal-title":"Osteoarthr Cartil"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1080\/08941939.2021.1953640","article-title":"Intervertebral disc degeneration models for pathophysiology and regenerative therapy -benefits and limitations","volume":"35","author":"Wang","year":"2022","journal-title":"J Investig Surg"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"e70046","DOI":"10.1111\/cpr.70046","article-title":"Engineering intervertebral disc regeneration: biomaterials, cell sources and animal models","volume":"58","author":"Yang","year":"2025","journal-title":"Cell Prolif"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3109\/03008200109005650","article-title":"Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation","volume":"42","author":"Johnson","year":"2001","journal-title":"Connect Tissue Res"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"104","DOI":"10.22203\/eCM.v030a08","article-title":"Disc in flames: roles of TNF-\u03b1 and IL-1\u03b2 in intervertebral disc degeneration","volume":"30","author":"Johnson","year":"2015","journal-title":"Eur Cell Mater"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"110660","DOI":"10.1016\/j.biopha.2020.110660","article-title":"The role of IL-1\u03b2 and TNF-\u03b1 in intervertebral disc degeneration","volume":"131","author":"Wang","year":"2020","journal-title":"Biomed Pharmacother"},{"key":"ref72","first-page":"634066","article-title":"Regulated cell death in intervertebral disc degeneration: apoptosis, necroptosis, and pyroptosis","volume":"9","author":"Fang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"ref73","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0140-6736(97)02135-1","article-title":"Nerve ingrowth into diseased intervertebral disc in chronic back pain","volume":"350","author":"Freemont","year":"1997","journal-title":"Lancet"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"ref75","first-page":"915","article-title":"Innervation of pathologies in the intervertebral disc and other spinal tissues: a review of mechanisms","volume":"28","author":"Fields","year":"2014","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.3390\/neurolint16060129","article-title":"Animal models of intervertebral disc diseases: advantages, limitations, and future directions","volume":"16","author":"Hong","year":"2024","journal-title":"Neurol Int"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"e1235","DOI":"10.1002\/jsp2.1235","article-title":"Controversies in spine research: organ culture versus in vivo models for studies of the intervertebral disc","volume":"5","author":"Tang","year":"2022","journal-title":"JOR Spine"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1753988\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:44:49Z","timestamp":1772023489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1753988\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":77,"alternative-id":["10.3389\/fmed.2026.1753988"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1753988","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]},"article-number":"1753988"}}