Intervertebral disc degeneration (IVDD) is a progressive, multifactorial condition in which the cellular and extracellular matrix architecture of the disc deteriorates. It is a leading global cause of chronic low back pain and disability. Its pathophysiology involves a complex interplay among cellular senescence, inflammatory signaling, oxidative stress, mitochondrial dysfunction, and impaired mechanotransduction. Recent studies have clarified the roles of mitophagy and programmed cell death pathways such as pyroptosis and ferroptosis, as well as the critical influence of the disc microenvironment on disease progression. Diagnosis depends mainly on magnetic resonance imaging, although emerging biomarkers and advanced imaging techniques may allow earlier detection. Clinical management follows a stepwise approach, starting with conservative measures and advancing to surgery for refractory cases. Traditional treatments focus on symptom relief, whereas emerging regenerative strategies including stem cell therapies, senolytics, and biomaterial innovations aim to modify the degenerative cascade at the molecular level. This review summarizes current knowledge of IVDD pathogenesis and assesses contemporary clinical management protocols together with promising biological therapies.
References
[1]
Ravindra, V.M., Senglaub, S.S., Rattani, A., Dewan, M.C., H？rtl, R., Bisson, E., et al. (2018) Degenerative Lumbar Spine Disease: Estimating Global Incidence and Worldwide Volume. Global Spine Journal, 8, 784-794. https://doi.org/10.1177/2192568218770769
[2]
(2023) Global, Regional, and National Burden of Low Back Pain, 1990-2020, Its Attributable Risk Factors, and Projections to 2050: A Systematic Analysis of the Global Burden of Disease Study 2021. The Lancet Rheumatology, 5, e316-e329.
[3]
Oei, M.W., Evens, A.L., Bhatt, A.A. and Garner, H.W. (2022) Imaging of the Aging Spine. Radiologic Clinics of North America, 60, 629-640. https://doi.org/10.1016/j.rcl.2022.03.006
[4]
Ou-Yang, D.C., Kleck, C.J. and Ackert-Bicknell, C.L. (2023) Genetics of Intervertebral Disc Degeneration. Current Osteoporosis Reports, 21, 56-64. https://doi.org/10.1007/s11914-022-00769-0
[5]
de Oliveira, C.A.A., Oliveira, B.S., Theodoro, R., Wang, J., Santos, G.S., Rodrigues, B.L., et al. (2024) Orthobiologic Management Options for Degenerative Disc Disease. Bioengineering, 11, Article No. 591. https://doi.org/10.3390/bioengineering11060591
[6]
Brinjikji, W., Luetmer, P.H., Comstock, B., Bresnahan, B.W., Chen, L.E., Deyo, R.A., et al. (2015) Systematic Literature Review of Imaging Features of Spinal Degeneration in Asymptomatic Populations. American Journal of Neuroradiology, 36, 811-816. https://doi.org/10.3174/ajnr.a4173
[7]
Z？bek, Z., Wycza？kowska-Tomasik, A., Pobo？y, K., Adamus, J.P., Turek, G., Z？bek, M., et al. (2025) Understanding the Microenvironment of Intervertebral Disc Degeneration: A Comprehensive Review of Pathophysiological Insights and Therapeutic Implications. International Journal of Molecular Sciences, 26, Article No. 9938. https://doi.org/10.3390/ijms26209938
[8]
Brinjikji, W., Diehn, F.E., Jarvik, J.G., Carr, C.M., Kallmes, D.F., Murad, M.H., et al. (2015) MRI Findings of Disc Degeneration Are More Prevalent in Adults with Low Back Pain than in Asymptomatic Controls: A Systematic Review and Meta-Analysis. American Journal of Neuroradiology, 36, 2394-2399. https://doi.org/10.3174/ajnr.a4498
[9]
Zhang, G., Li, L., Yang, Z., Cao, Z., Hu, X., Wang, Y., et al. (2025) BRD4/MAP2K7/PGF Signaling Axis Promotes Senescence and Extracellular Matrix Metabolism of Nucleus Pulposus Cells in Intervertebral Disk Degeneration. Aging Cell, 24, e70034. https://doi.org/10.1111/acel.70034
[10]
Yan, X., Ding, J., Zhang, R., Zhang, H., Kang, L., Jia, C., et al. (2024) FSTL1 Accelerates Nucleus Pulposus Cell Senescence and Intervertebral Disc Degeneration through TLR4/NF-κB Pathway. Inflammation, 47, 1229-1247. https://doi.org/10.1007/s10753-024-01972-0
[11]
Sidhu, G.S., Henkelman, E., Vaccaro, A.R., Albert, T.J., Hilibrand, A., Anderson, G.D., et al. (2014) Minimally Invasive versus Open Posterior Lumbar Interbody Fusion: A Systematic Review. Clinical Orthopaedics & Related Research, 472, 1792-1799. https://doi.org/10.1007/s11999-014-3619-5
[12]
Kou, Y., Chang, J., Guan, X., Chang, Q. and Feng, H. (2021) Endoscopic Lumbar Interbody Fusion and Minimally Invasive Transforaminal Lumbar Interbody Fusion for the Treatment of Lumbar Degenerative Diseases: A Systematic Review and Meta-Analysis. World Neurosurgery, 152, e352-e368. https://doi.org/10.1016/j.wneu.2021.05.109
[13]
Gong, Y., Cheng, Z., He, J., Gan, Y., Jiang, X. and Liu, J. (2026) Etiology, Diagnosis and Treatment of Lumbar Disc Degeneration: A Focus on the Mechanism of Action of Piezo1 and Research Perspectives. Frontiers in Cell and Developmental Biology, 14, Article ID: 1679466. https://doi.org/10.3389/fcell.2026.1679466
[14]
Elmounedi, N., Bahloul, W. and Keskes, H. (2024) Current Therapeutic Strategies of Intervertebral Disc Regenerative Medicine. Molecular Diagnosis & Therapy, 28, 745-775. https://doi.org/10.1007/s40291-024-00729-7
[15]
Qiao, H., Chen, T., Yu, J., Li, C., Gao, C., Yang, Y., et al. (2026) Decoding Intervertebral Disc Degeneration Pathomechanics: From Mechanisms to Therapeutic Horizons. Journal of Advanced Research, 88, 381-400. https://doi.org/10.1016/j.jare.2026.01.045
[16]
Shankar, H., Scarlett, J.A. and Abram, S.E. (2009) Anatomy and Pathophysiology of Intervertebral Disc Disease. Techniques in Regional Anesthesia and Pain Management, 13, 67-75. https://doi.org/10.1053/j.trap.2009.05.001
[17]
McCann, M.R., Tamplin, O.J., Rossant, J. and Séguin, C.A. (2012) Tracing Notochord-Derived Cells Using a noto-Cre Mouse: Implications for Intervertebral Disc Development. Disease Models & Mechanisms, 5, 73-82. https://doi.org/10.1242/dmm.008128
[18]
Johnson, W.E.B. and Roberts, S. (2003) Human Intervertebral Disc Cell Morphology and Cytoskeletal Composition: A Preliminary Study of Regional Variations in Health and Disease. Journal of Anatomy, 203, 605-612. https://doi.org/10.1046/j.1469-7580.2003.00249.x
[19]
Shi, C., Fan, Y., Huang, X., Fan, M., Zhao, L., Zhang, H., et al. (2024) Single-Cell RNA Sequencing Reveals the Differentiation and Regulation of Endplate Cells in Human Intervertebral Disc Degeneration. Scientific Reports, 14, Article No. 21414. https://doi.org/10.1038/s41598-024-71891-5
[20]
Li, B., Zhang, Y., Ji, C., Shi, Z. and Li, N. (2026) Mesenchymal Stem Cell and Exosome-Based Therapies for Degenerative Disc Disease: From Mechanisms to Clinical Translation. Frontiers in Cell and Developmental Biology, 14, Article ID: 1802828. https://doi.org/10.3389/fcell.2026.1802828
[21]
Yang, H., Chen, X., Chen, J., Dong, Y., Huang, Y., Qin, L., et al. (2024) The Pathogenesis and Targeted Therapies of Intervertebral Disc Degeneration Induced by Cartilage Endplate Inflammation. Frontiers in Cell and Developmental Biology, 12, 1492870. https://doi.org/10.3389/fcell.2024.1492870
[22]
Mehta, R., Mohanty, S., Hallmark, A.P., Shah, V., Ross, T., Bogner, E.A., et al. (2025) Age and Spinal Level as Predictors of Lumbar Disc Degeneration in Humans and Mice: A Comparative Analysis. JOR SPINE, 8, e70122. https://doi.org/10.1002/jsp2.70122
[23]
Mokhtari, K. (2026) Molecular and Cellular Mechanisms of Intervertebral Disc Degeneration: A Narrative Mini-Review. Journal of Research in Orthopedic Science, 13, 1-4. https://doi.org/10.32598/jrosj.13.1.2718.3
[24]
Massey, C.J., van Donkelaar, C.C., Vresilovic, E., Zavaliangos, A. and Marcolongo, M. (2012) Effects of Aging and Degeneration on the Human Intervertebral Disc during the Diurnal Cycle: A Finite Element Study. Journal of Orthopaedic Research, 30, 122-128. https://doi.org/10.1002/jor.21475
[25]
Johnson, Z., Schoepflin, Z., Choi, H., Shapiro, I. and Risbud, M. (2015) Disc in Flames: Roles of TNF-α and IL-1β in Intervertebral Disc Degeneration. European Cells and Materials, 30, 104-117. https://doi.org/10.22203/ecm.v030a08
[26]
Bermudez-Lekerika, P., Crump, K.B., Tseranidou, S., Nüesch, A., Kanelis, E., Alminnawi, A., et al. (2022) Immuno-Modulatory Effects of Intervertebral Disc Cells. Frontiers in Cell and Developmental Biology, 10, Article ID: 924692. https://doi.org/10.3389/fcell.2022.924692
[27]
Sun, Z., Liu, B. and Luo, Z. (2020) The Immune Privilege of the Intervertebral Disc: Implications for Intervertebral Disc Degeneration Treatment. International Journal of Medical Sciences, 17, 685-692. https://doi.org/10.7150/ijms.42238
[28]
Burt, K.G., Kim, M.K.M., Viola, D.C., Abraham, A.C. and Chahine, N.O. (2024) Nuclear Factor κB Overactivation in the Intervertebral Disc Leads to Macrophage Recruitment and Severe Disc Degeneration. Science Advances, 10, eadj3194. https://doi.org/10.1126/sciadv.adj3194
[29]
Lin, J., Ma, J., Wang, Z., Xu, C., Sun, Y., Miao, Z., et al. (2025) DBC1 Promotes Intervertebral Disc Degeneration by Activating NF-κB Pathway and Inhibiting SIRT1 Activity. Life Sciences, 373, Article ID: 123689. https://doi.org/10.1016/j.lfs.2025.123689
[30]
Guan, Y., Bai, X., Li, C., Zhang, Z., He, Q., Chen, L., et al. (2026) The Role and Potential Therapeutic Intervention of Cellular Senescence in Intervertebral Disc Degeneration. Genes & Diseases, 13, Article ID: 101871. https://doi.org/10.1016/j.gendis.2025.101871
[31]
Xiang, M., Peng, Q., Dai, F., Wu, Y., Liu, L. and Liu, H. (2025) Machine Learning-Enabled Identification of Nucleus Pulposus Senescence-Associated Genes as Potential Biomarkers for Intervertebral Disc Degeneration. European Journal of Medical Research, 30, Article No. 887. https://doi.org/10.1186/s40001-025-03102-4
[32]
Hao, H., Liang, W., Zhang, S., Cai, X., Yakefu, A., Gao, S., et al. (2025) Ruxolitinib Delays Nucleus Pulposus Cell Senescence in Rat Intervertebral Discs. JOR SPINE, 8, e70044. https://doi.org/10.1002/jsp2.70044
[33]
Sun, K., Kang, Z., Yan, C., Yu, Y., Han, L., Shi, Y., et al. (2025) Rescuing ACE2-Deficiency-Mediated Nucleus Pulposus Senescence and Intervertebral Disc Degeneration by a Nanotopology-Enhanced RNAi System. Advanced Science, 12, Article ID: 2412908. https://doi.org/10.1002/advs.202412908
[34]
Xing, Q., Liang, Q., Bian, Q., Ding, D., Cui, X., Shi, Q., et al. (2010) Leg Amputation Accelerates Senescence of Rat Lumbar Intervertebral Discs. Spine, 35, E1253-E1261. https://doi.org/10.1097/brs.0b013e3181e7d087
[35]
Wu, W., Cheng, Z., Chen, X., Shi, P., Zhang, A., Gao, H., et al. (2026) Pyroptosis: Mechanism and Therapeutic Strategies with Intervertebral Disc Degeneration. Experimental & Molecular Medicine, 58, 99-109. https://doi.org/10.1038/s12276-025-01630-x
[36]
Luo, J., Yang, Y., Wang, X., Chang, X. and Fu, S. (2022) Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications. Biomolecules, 12, Article No. 1804. https://doi.org/10.3390/biom12121804
[37]
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J. and Guo, Y. (2026) Mitochondria-Driven Ferroptosis in Intervertebral Disc Degeneration: A Novel Target in Age-Related Spinal Diseases (Review). Experimental and Therapeutic Medicine, 31, Article No. 88. https://doi.org/10.3892/etm.2026.13083
[38]
Zhu, D., Wang, Z., Chen, S., Li, Y. and Kang, X. (2025) Therapeutic Potential of Targeting the IRF2/POSTN/Notch1 Axis in Nucleus Pulposus Cells for Intervertebral Disc Degeneration. Journal of Neuroinflammation, 22, Article No. 13. https://doi.org/10.1186/s12974-025-03335-4
[39]
Zhang, C., Li, C. and Jiang, Q. (2025) Role of Oxidative Stress in Intervertebral Disc Degeneration: Mechanisms, Pathogenesis, and Therapeutic Strategies. Molecular Biology Reports, 52, Article No. 444. https://doi.org/10.1007/s11033-025-10538-8
[40]
Yang, Y., Li, H., Zuo, J. and Lei, F. (2025) Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi-Axial Perspective of Mechanical, Immune, and Metabolic Pathways. JOR SPINE, 8, e70089. https://doi.org/10.1002/jsp2.70089
[41]
Hao, P., He, Y., Li, F., Luo, Y., Song, C., Liu, Z., et al. (2026) Research on the Molecular Mechanism of Intervertebral Disc Degeneration Caused by Mitochondrial Dysfunction. Tissue and Cell, 98, Article ID: 103155. https://doi.org/10.1016/j.tice.2025.103155
[42]
Zhang, X., Zhang, Z., Zou, X., Wang, Y., Qi, J., Han, S., et al. (2024) Unraveling the Mechanisms of Intervertebral Disc Degeneration: An Exploration of the p38 MAPK Signaling Pathway. Frontiers in Cell and Developmental Biology, 11, Article ID: 1324561. https://doi.org/10.3389/fcell.2023.1324561
[43]
Cheng, X., Ni, B., Zhang, F., Hu, Y. and Zhao, J. (2016) High Glucose-Induced Oxidative Stress Mediates Apoptosis and Extracellular Matrix Metabolic Imbalances Possibly via P38 MAPK Activation in Rat Nucleus Pulposus Cells. Journal of Diabetes Research, 2016, Article ID: 3765173. https://doi.org/10.1155/2016/3765173
[44]
Wu, Z., Liu, Y., Song, W., Zhou, K., Ling, Y. and Zhang, H. (2025) Role of Mitophagy in Intervertebral Disc Degeneration: A Narrative Review. Osteoarthritis and Cartilage, 33, 27-41. https://doi.org/10.1016/j.joca.2024.09.013
[45]
Song, Y., Liang, H., Li, G., Ma, L., Zhu, D., Zhang, W., et al. (2024) The NLRX1-SLC39A7 Complex Orchestrates Mitochondrial Dynamics and Mitophagy to Rejuvenate Intervertebral Disc by Modulating Mitochondrial Zn2+ Trafficking. Autophagy, 20, 809-829. https://doi.org/10.1080/15548627.2023.2274205
[46]
Sun, K., Jing, X., Guo, J., Yao, X. and Guo, F. (2020) Mitophagy in Degenerative Joint Diseases. Autophagy, 17, 2082-2092. https://doi.org/10.1080/15548627.2020.1822097
[47]
Ke, W., Xu, H., Zhang, C., Liao, Z., Liang, H., Tong, B., et al. (2025) An Overview of Mechanical Microenvironment and Mechanotransduction in Intervertebral Disc Degeneration. Experimental & Molecular Medicine, 57, 2157-2168. https://doi.org/10.1038/s12276-025-01546-6
[48]
Kumar, R., Sporn, K., Kaur, H., Khanna, A., Paladugu, P., Zaman, N., et al. (2025) Current Mechanobiological Pathways and Therapies Driving Spinal Health. Bioengineering, 12, Article No. 886. https://doi.org/10.3390/bioengineering12080886
[49]
Shi, Z.-W., et al. (2023) Roles of Hippo-YAP/TAZ Signalling in Intervertebral Disc Degeneration. Biomedicine & Pharmacotherapy, 159, Article ID: 114099. https://doi.org/10.1016/j.biopha.2022.114099
[50]
Fearing, B.V., Jing, L., Barcellona, M.N., Witte, S.E., Buchowski, J.M., Zebala, L.P., et al. (2019) Mechanosensitive Transcriptional Coactivators MRTF-A and YAP/TAZ Regulate Nucleus Pulposus Cell Phenotype through Cell Shape. The FASEB Journal, 33, 14022-14035. https://doi.org/10.1096/fj.201802725rrr
[51]
Yu, Q., Zhu, Z., Wang, Y., Duan, Y., Liu, C., Hong, Y., et al. (2026) From Disease Model to Therapeutic Insight: An Engineered Hydrogel Reveals the Role of Matrix Viscous Dissipation in Intervertebral Disc Degeneration. Bioactive Materials, 61, 408-428. https://doi.org/10.1016/j.bioactmat.2026.02.021
[52]
Mark Kim, M.K., Lawrence, M., Quinonez, D., Brooks, C., Ramachandran, R. and Séguin, C.A. (2024) Transient Receptor Potential Vanilloid 4 Regulates Extracellular Matrix Composition and Mediates Load-Induced Intervertebral Disc Degeneration in a Mouse Model. Osteoarthritis and Cartilage, 32, 881-894. https://doi.org/10.1016/j.joca.2024.04.001
[53]
Li, F., Chen, M., Zhang, M., Chen, S., Qu, M., He, S., et al. (2025) Targeting Piezo1 Channel to Alleviate Intervertebral Disc Degeneration. Journal of Orthopaedic Translation, 51, 145-158. https://doi.org/10.1016/j.jot.2025.01.006
[54]
Sun, Y., Leng, P., Song, M., Li, D., Guo, P., Xu, X., et al. (2020) Piezo1 Activates the NLRP3 Inflammasome in Nucleus Pulposus Cell-Mediated by Ca(2+)/NF-κB Pathway. International Immunopharmacology, 85, Article ID: 106681. https://doi.org/10.1016/j.intimp.2020.106681
[55]
Sun, Y., Li, Z., Duan, J., Liu, E., Yang, L., Sun, F., et al. (2024) From Structure to Therapy: The Critical Influence of Cartilaginous Endplates and Microvascular Network on Intervertebral Disc Degeneration. Frontiers in Bioengineering and Biotechnology, 12, Article ID: 1489420. https://doi.org/10.3389/fbioe.2024.1489420
[56]
Mokhbi Soukane, D., Shirazi-Adl, A. and Urban, J.P.G. (2009) Investigation of Solute Concentrations in a 3D Model of Intervertebral Disc. European Spine Journal, 18, 254-262. https://doi.org/10.1007/s00586-008-0822-7
[57]
Wu, Y., et al. (2013) Effect of Cartilage Endplate on Cell Based Disc Regeneration: A Finite Element Analysis. Molecular & Cellular Biomechanics, 10, 159-182.
[58]
Liu, Y., Huang, H., Lin, M., Yang, C., Shen, T. and Zhou, H. (2026) From Modic Changes to the Disc-Endplate-Bone Marrow Complex: Imaging Stratification, Immune Remodeling, and Translational Implications in Intervertebral Disc Degeneration. Frontiers in Immunology, 17, Article ID: 1906279. https://doi.org/10.3389/fimmu.2026.1906279
[59]
Sambrook, P.N., MacGregor, A.J. and Spector, T.D. (1999) Genetic Influences on Cervical and Lumbar Disc Degeneration: A Magnetic Resonance Imaging Study in Twins. Arthritis & Rheumatism, 42, 366-372. https://doi.org/10.1002/1529-0131(199902)42:2<366::aid-anr20>3.0.co;2-6
[60]
Zeng, B., Xu, S., Zhou, D., Chen, R., Ding, Y., Wu, Z., et al. (2025) Unraveling the Causal Landscape of Intervertebral Disc Degeneration: A Mendelian Randomization Analysis of 108 Traits. Medicine, 104, e45603. https://doi.org/10.1097/md.0000000000045603
[61]
Seki, S., Kawaguchi, Y., Chiba, K., Mikami, Y., Kizawa, H., Oya, T., et al. (2005) A Functional SNP in CILP, Encoding Cartilage Intermediate Layer Protein, Is Associated with Susceptibility to Lumbar Disc Disease. Nature Genetics, 37, 607-612. https://doi.org/10.1038/ng1557
[62]
Min, S., Nakazato, K., Yamamoto, Y., Gushiken, K., Fujimoto, H., Fujishiro, H., et al. (2010) Cartilage Intermediate Layer Protein Gene Is Associated with Lumbar Disc Degeneration in Male, but Not Female, Collegiate Athletes. The American Journal of Sports Medicine, 38, 2552-2557. https://doi.org/10.1177/0363546510376714
[63]
Min, S., Nakazato, K., Ishigami, H. and Hiranuma, K. (2013) Cartilage Intermediate Layer Protein and Asporin Polymorphisms Are Independent Risk Factors of Lumbar Disc Degeneration in Male Collegiate Athletes. Cartilage, 5, 37-42. https://doi.org/10.1177/1947603513500786
[64]
Hou, Y., Zhao, T., Guo, Y. and Shi, J. (2025) Macrophage Reprogramming as a Therapeutic Avenue in Intervertebral Disc Degeneration: Insights into Pharmacological Targeting. Biochemical and Biophysical Research Communications, 780, Article ID: 152489. https://doi.org/10.1016/j.bbrc.2025.152489
[65]
Xu, J., Gu, H., Zhou, K., Wu, L., Zhang, Y., Bian, C., et al. (2025) ZIP8 Regulates Inflammation and Macrophage Polarisation in Intervertebral Disc Degeneration via the Wnt/β-Catenin Pathway. Journal of Cellular and Molecular Medicine, 29, e70431. https://doi.org/10.1111/jcmm.70431
[66]
Zhang, K., Du, L., Li, Z., Huo, Z., Shen, L., Gao, S., et al. (2024) M2 Macrophage-Derived Small Extracellular Vesicles Ameliorate Pyroptosis and Intervertebral Disc Degeneration. Biomaterials Research, 28, Article No. 0047. https://doi.org/10.34133/bmr.0047
[67]
Luo, J., Jin, G., Cui, S., Wang, H. and Liu, Q. (2025) Regulating Macrophage Phenotypes with IL4I1-Mimetic Nanoparticles in IDD Treatment. Journal of Nanobiotechnology, 23, Article No. 175. https://doi.org/10.1186/s12951-025-03241-0
Ren, J., Wang, X., Zhou, X. and Fan, X. (2026) Senescence-Associated Secretory Phenotype: The “Pathogenic” Factor Driving Orthopedic Degenerative Diseases and Its Regulation. Frontiers in Aging, 7, Article ID: 1818021. https://doi.org/10.3389/fragi.2026.1818021
[70]
Guo, D., Xiao, L., Li, H., Pan, Y. and Zhang, H. (2026) Rebuilding the Degenerative Disc Microenvironment: Mesenchymal Stem Cells, Exosomes, and Bioengineered Scaffolds. Frontiers in Bioengineering and Biotechnology, 14, Article ID: 1802866. https://doi.org/10.3389/fbioe.2026.1802866
[71]
Sun, R., Zhou, Y., Wu, X., Shi, H., Wang, F., Gao, J., et al. (2026) N6-Methylation Modification: Its Role in Regulating Cell Senescence and Inflammation in Osteoarthritis and Intervertebral Disc Degeneration. DNA and Cell Biology, 45, 105-115. https://doi.org/10.1177/10445498251411282
Genevay, S., Courvoisier, D.S., Konstantinou, K., Kovacs, F.M., Marty, M., Rainville, J., et al. (2017) Clinical Classification Criteria for Radicular Pain Caused by Lumbar Disc Herniation: The Radicular Pain Caused by Disc Herniation (RAPIDH) Criteria. The Spine Journal, 17, 1464-1471. https://doi.org/10.1016/j.spinee.2017.05.005
[74]
Altkorn, D. (2020) Lumbar Radiculopathy Due to a Herniated Disk. In: Stern, S.D.C., Cifu, A.S. and Altkorn, D., Symptom to Diagnosis: An Evidence-Based Guide, 4th Edition, McGraw-Hill Education, 127-128.
[75]
Tamagawa, S., Sakai, D., Nojiri, H., Sato, M., Ishijima, M. and Watanabe, M. (2022) Imaging Evaluation of Intervertebral Disc Degeneration and Painful Discs—Advances and Challenges in Quantitative MRI. Diagnostics, 12, Article No. 707. https://doi.org/10.3390/diagnostics12030707
[76]
Teichner, E.M., Subtirelu, R.C., Crutchfield, C.R., Parikh, C., Ashok, A., Talasila, S., et al. (2025) The Advancement and Utility of Multimodal Imaging in the Diagnosis of Degenerative Disc Disease. Frontiers in Radiology, 5, Article ID: 1298054. https://doi.org/10.3389/fradi.2025.1298054
[77]
Pfirrmann, C.W.A., Metzdorf, A., Zanetti, M., Hodler, J. and Boos, N. (2001) Magnetic Resonance Classification of Lumbar Intervertebral Disc Degeneration. Spine, 26, 1873-1878. https://doi.org/10.1097/00007632-200109010-00011
[78]
Murto, N., Lund, T., Kautiainen, H., Luoma, K. and Kerttula, L. (2025) Comparison of Lumbar Disc Degeneration Grading between Deep Learning Model Spinenet and Radiologist: A Longitudinal Study with a 14-Year Follow-Up. European Spine Journal, 34, 3767-3773. https://doi.org/10.1007/s00586-025-08900-2
[79]
Barnes, N.A., Dkhar, W., Kadavigere, R., Sukumar, S., Pradhan, A., P.S., P., et al. (2025) Exploring Mean Kurtosis in MR Diffusion Kurtosis Imaging for Early Detection of Lumbar Spine Degeneration: A Systematic Review. F1000Research, 14, Article No. 440. https://doi.org/10.12688/f1000research.163638.2
[80]
Huang, K., Shen, L., Guan, H., Dai, L., Huang, X., Zhang, X., et al. (2025) Construction of a lncRNA-miRNA-mRNA Network for Biomarker Identification in Intervertebral Disc Degeneration. Journal of Musculoskeletal and Neuronal Interactions, 25, 316-327. https://doi.org/10.22540/jmni-25-316
[81]
Shi, Y., Guo, R., Zeng, Y., Fang, Q., Wang, X., Liu, W., et al. (2022) SNHG5/miR-299-5p/ATF2 Axis as a Biomarker in Immune Microenvironment of Intervertebral Disc Degeneration. Mediators of Inflammation, 2022, Article ID: 2558275. https://doi.org/10.1155/2022/2558275
[82]
Zhang, R., Liang, Y., Zhang, C., Liu, Y. and Hong, Y. (2026) Diagnostic Evidence in Suspected Discogenic Low Back Pain: A Pain-Source Attribution Perspective. Frontiers in Medicine, 13, Article ID: 1924460. https://doi.org/10.3389/fmed.2026.1924460
[83]
Dua, A., Stretanski, M.F. and Vu, L. (2026) Lumbar Provocative Discography. StatPearls Publishing.
[84]
Wolfer, L. (2008) Systematic Review of Lumbar Provocation Discography in Asymptomatic Subjects with a Meta-Analysis of False-Positive Rates. Pain Physician, 4, 513-538. https://doi.org/10.36076/ppj.2008/11/513
[85]
Kaiser, M.G., Eck, J.C., Groff, M.W., Watters, W.C., Dailey, A.T., Resnick, D.K., et al. (2014) Guideline Update for the Performance of Fusion Procedures for Degenerative Disease of the Lumbar Spine. Part 1: Introduction and Methodology. Journal of Neurosurgery: Spine, 21, 2-6. https://doi.org/10.3171/2014.4.spine14257
[86]
Bratton, R.L. (1999) Assessment and Management of Acute Low Back Pain. American Family Physician, 60, 2299-2308.
[87]
Lu, Y., Guzman, J.Z., Purmessur, D., Iatridis, J.C., Hecht, A.C., Qureshi, S.A., et al. (2014) Nonoperative Management of Discogenic Back Pain: A Systematic Review. Spine, 39, 1314-1324. https://doi.org/10.1097/brs.0000000000000401
[88]
Wai, E.K., Rodriguez, S., Dagenais, S. and Hall, H. (2008) Evidence-Informed Management of Chronic Low Back Pain with Physical Activity, Smoking Cessation, and Weight Loss. The Spine Journal, 8, 195-202. https://doi.org/10.1016/j.spinee.2007.10.024
[89]
Geng, J., Li, L., Liu, T., Yan, B. and Peng, L. (2024) Management and Nursing Approaches to Low Back Pain: Investigating the Causal Association with Lifestyle-Related Risk Factors. Pain Management Nursing, 25, 300-307. https://doi.org/10.1016/j.pmn.2024.01.001
[90]
Zhang, C., Li, Y., Zhong, Y., Feng, C., Zhang, Z. and Wang, C. (2021) Effectiveness of Motor Control Exercise on Non-Specific Chronic Low Back Pain, Disability and Core Muscle Morphological Characteristics: A Meta-Analysis of Randomized Controlled Trials. European Journal of Physical and Rehabilitation Medicine, 57, 793-806. https://doi.org/10.23736/s1973-9087.21.06555-2
[91]
Smith, B.E., Littlewood, C. and May, S. (2014) An Update of Stabilisation Exercises for Low Back Pain: A Systematic Review with Meta-Analysis. BMC Musculoskeletal Disorders, 15, Article No. 416. https://doi.org/10.1186/1471-2474-15-416
[92]
Sharif, S., Jazaib Ali, M.Y., Kirazl？, Y., Vlok, I., Zygourakis, C. and Zileli, M. (2024) Acute Back Pain: The Role of Medication, Physical Medicine and Rehabilitation: WFNS Spine Committee Recommendations. World Neurosurgery: X, 23, Article ID: 100273. https://doi.org/10.1016/j.wnsx.2024.100273
[93]
van Tulder, M.W., et al. (2000) Non-Steroidal Anti-Inflammatory Drugs for Low Back Pain. The Cochrane Database of Systematic Reviews, No. 2, Cd000396.
[94]
Scheiman, J.M. and Fendrick, A.M. (2005) Practical Approaches to Minimizing Gastrointestinal and Cardiovascular Safety Concerns with COX-2 Inhibitors and NSAIDs. Arthritis Research & Therapy, 7, S23-S29. https://doi.org/10.1186/ar1795
[95]
Saragiotto, B.T., et al. (2016) Paracetamol for Low Back Pain. The Cochrane Database of Systematic Reviews, 2016, CD012230.
[96]
Nury, E., Schmucker, C., Nagavci, B., Motschall, E., Nitschke, K., Schulte, E., et al. (2022) Efficacy and Safety of Strong Opioids for Chronic Noncancer Pain and Chronic Low Back Pain: A Systematic Review and Meta-Analyses. Pain, 163, 610-636. https://doi.org/10.1097/j.pain.0000000000002423
[97]
Crofford, L.J. (2010) Adverse Effects of Chronic Opioid Therapy for Chronic Musculoskeletal Pain. Nature Reviews Rheumatology, 6, 191-197. https://doi.org/10.1038/nrrheum.2010.24
[98]
Oliveira, C.B., Maher, C.G., Ferreira, M.L., Hancock, M.J., Oliveira, V.C., McLachlan, A.J., et al. (2020) Epidural Corticosteroid Injections for Lumbosacral Radicular Pain. Cochrane Database of Systematic Reviews, 2020, CD013577. https://doi.org/10.1002/14651858.cd013577
[99]
Cervera-Irimia, J. and Tomé-Bermejo, F. (2013) Caudal Epidural Steroid Injection in the Treatment of Chronic Discogenic Low Back Pain. Comparative, Prospective and Randomized Study. Revista Espa？ola de Cirugía Ortopédica y Traumatología (English Edition), 57, 324-332. https://doi.org/10.1016/j.recote.2013.05.002
[100]
Macedo, L.G., Hum, A., Kuleba, L., Mo, J., Truong, L., Yeung, M., et al. (2013) Physical Therapy Interventions for Degenerative Lumbar Spinal Stenosis: A Systematic Review. Physical Therapy, 93, 1646-1660. https://doi.org/10.2522/ptj.20120379
[101]
Ammendolia, C., Hofkirchner, C., Plener, J., Bussières, A., Schneider, M.J., Young, J.J., et al. (2022) Non-Operative Treatment for Lumbar Spinal Stenosis with Neurogenic Claudication: An Updated Systematic Review. BMJ Open, 12, e057724. https://doi.org/10.1136/bmjopen-2021-057724
[102]
Faughender, J., Koehler, P., Kitei, P., Hsu, V. and Stolzenberg, D. (2025) A Staged Approach to Treating Chronic Low Back and Radicular Pain: Basivertebral Nerve Ablation in Conjunction with Surgical Decompression: A Case Report. Interventional Pain Medicine, 4, Article ID: 100545. https://doi.org/10.1016/j.inpm.2025.100545
[103]
Hooten, W.M. and Cohen, S.P. (2015) Evaluation and Treatment of Low Back Pain: A Clinically Focused Review for Primary Care Specialists. Mayo Clinic Proceedings, 90, 1699-1718. https://doi.org/10.1016/j.mayocp.2015.10.009
[104]
Monsef, J.B. and Techy, F. (2017) Patient Selection for Spine Surgery. In: Steinmetz, M.P. and Benzel, E.C., Eds., Benzel’s Spine Surgery, 2-Volume Set, Elsevier, 219-224.e2. https://doi.org/10.1016/b978-0-323-40030-5.00025-3
[105]
Botwin, K.P., Gruber, R.D. and Savarese, R. (2005) Lumbar Discography. Techniques in Regional Anesthesia and Pain Management, 9, 3-12. https://doi.org/10.1053/j.trap.2005.01.001
[106]
Thalgott, J.S., Albert, T.J., Vaccaro, A.R., Aprill, C.N., Giuffre, J.M., Drake, J.S., et al. (2004) A New Classification System for Degenerative Disc Disease of the Lumbar Spine Based on Magnetic Resonance Imaging, Provocative Discography, Plain Radiographs and Anatomic Considerations. The Spine Journal, 4, S167-S172. https://doi.org/10.1016/j.spinee.2004.07.001
[107]
Weinstein, J.N., Tosteson, T.D., Lurie, J.D., Tosteson, A.N.A., Blood, E., Hanscom, B., et al. (2008) Surgical versus Nonsurgical Therapy for Lumbar Spinal Stenosis. New England Journal of Medicine, 358, 794-810. https://doi.org/10.1056/nejmoa0707136
[108]
Cavu？o？lu, H., et al. (2007) Efficacy of Unilateral Laminectomy for Bilateral Decompression in Lumbar Spinal Stenosis. Turkish Neurosurgery, 17, 100-108.
[109]
Usman, M., et al. (2013) Unilateral Approach for Bilateral Decompression of Lumbar Spinal Stenosis: A Minimal Invasive Surgery. Journal of College of Physicians and Surgeons Pakistan, 23, 852-856.
[110]
Derman, P.B. and Albert, T.J. (2017) Interbody Fusion Techniques in the Surgical Management of Degenerative Lumbar Spondylolisthesis. Current Reviews in Musculoskeletal Medicine, 10, 530-538. https://doi.org/10.1007/s12178-017-9443-2
[111]
Teng, I., Han, J., Phan, K. and Mobbs, R. (2017) A Meta-Analysis Comparing ALIF, PLIF, TLIF and LLIF. Journal of Clinical Neuroscience, 44, 11-17. https://doi.org/10.1016/j.jocn.2017.06.013
[112]
Nú？ez, J.H., Escudero, B., Omiste, I., Martínez-Pe？as, J., Surroca, M., Alonzo-González, F., et al. (2023) Outcomes of Cervical Arthroplasty versus Anterior Cervical Arthrodesis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials with a Minimum Follow-Up of 7-Year. European Journal of Orthopaedic Surgery & Traumatology, 33, 1875-1884. https://doi.org/10.1007/s00590-022-03365-1
[113]
Wang, Q., Tu, Z., Hu, P., Kontos, F., Li, Y., Li, L., et al. (2019) Long-Term Results Comparing Cervical Disc Arthroplasty to Anterior Cervical Discectomy and Fusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Orthopaedic Surgery, 12, 16-30. https://doi.org/10.1111/os.12585
[114]
Nabhan, A., Steudel, W.I., Nabhan, A., Pape, D. and Ishak, B. (2007) Segmental Kinematics and Adjacent Level Degeneration Following Disc Replacement versus Fusion: RCT with Three Years of Follow-up. Journal of Long-Term Effects of Medical Implants, 17, 229-236. https://doi.org/10.1615/jlongtermeffmedimplants.v17.i3.60
[115]
R？llinghoff, M., et al. (2012) Quality of Life and Radiological Outcome after Cervical Cage Fusion and Cervical Disc Arthroplasty. Acta Orthopaedica Belgica, 78, 369-375.
[116]
Park, P., Garton, H.J., Gala, V.C., Hoff, J.T. and McGillicuddy, J.E. (2004) Adjacent Segment Disease after Lumbar or Lumbosacral Fusion: Review of the Literature. Spine, 29, 1938-1944. https://doi.org/10.1097/01.brs.0000137069.88904.03
[117]
Jokeit, M., Tsagkaris, C., Altorfer, F.C.S., Cornaz, F., Snedeker, J.G., Farshad, M., et al. (2025) Impact of Iatrogenic Alterations on Adjacent Segment Degeneration after Lumbar Fusion Surgery: A Systematic Review. Journal of Orthopaedic Surgery and Research, 20, Article No. 425. https://doi.org/10.1186/s13018-025-05561-1
[118]
Luo, J., Gong, M., Huang, S., Yu, T. and Zou, X. (2015) Incidence of Adjacent Segment Degeneration in Cervical Disc Arthroplasty versus Anterior Cervical Decompression and Fusion Meta-Analysis of Prospective Studies. Archives of Orthopaedic and Trauma Surgery, 135, 155-160. https://doi.org/10.1007/s00402-014-2125-2
[119]
Wang, J.C., Arnold, P.M., Hermsmeyer, J.T. and Norvell, D.C. (2012) Do Lumbar Motion Preserving Devices Reduce the Risk of Adjacent Segment Pathology Compared with Fusion Surgery? A Systematic Review. Spine, 37, S133-S143. https://doi.org/10.1097/brs.0b013e31826cadf2
[120]
Heo, D.H., Cho, Y.J., Cho, S.M., Choi, H.C. and Kang, S.H. (2012) Adjacent Segment Degeneration after Lumbar Dynamic Stabilization Using Pedicle Screws and a Nitinol Spring Rod System with 2-Year Minimum Follow-Up. Journal of Spinal Disorders & Techniques, 25, 409-414. https://doi.org/10.1097/bsd.0b013e318231665d
[121]
Ran, K.R., Azad, T.D., Pahwa, B., Bernhardt, L.J. and Bydon, A. (2024) Index-Level Fusion and Adjacent Segment Disease Following Dynamic Stabilization for Lumbar Degenerative Disc Disease: Illustrative Case. Journal of Neurosurgery: Case Lessons, 8, CASE24179. https://doi.org/10.3171/case24179
[122]
Ferraz, V.R., Goulart, C.R., de Souza, M.F.R.F.F., Furlan, M.O.C.d.S., Mercier, P. and Mattei, T.A. (2026) Stem Cell Therapy for Degenerative Disc Disease: A Systematic Review of Preclinical Evidence, Clinical Translation, and Future Directions. North American Spine Society Journal (NASSJ), 25, Article ID: 100841. https://doi.org/10.1016/j.xnsj.2025.100841
[123]
Li, Z., Li, H., Ruan, Y., Wang, P., Zhu, M., Fu, W., et al. (2025) Stem Cell Therapy for Intervertebral Disc Degeneration: Clinical Progress with Exosomes and Gene Vectors. World Journal of Stem Cells, 17, Article ID: 102945. https://doi.org/10.4252/wjsc.v17.i4.102945
[124]
Maal, A.B., Kordi, R., Madani, H., Khadivi, M., Moghadam, N., Asnaashari, A., et al. (2025) Intradiscal Injection of Allogeneic Bone Marrow Derived Clonal Mesenchymal Stromal Cells in Discogenic Low Back Pain: A Phase I Study on Safety and Feasibility (RELIEF: Phase I). Stem Cell Research & Therapy, 16, Article No. 525. https://doi.org/10.1186/s13287-025-04606-w
[125]
Wang, J., Ran, B. and Wei, J. (2025) Engineered Extracellular Vesicles for Intervertebral Disc Regeneration: Mechanisms, Strategies, and Translational Potential. Cureus, 17, e97119. https://doi.org/10.7759/cureus.97119
[126]
Laagland, L.T., Salzer, E., Fabra, G.T., Tong, X., Poramba-Liyanage, D.W.L., Warin, J., et al. (2026) A Bioactive Hydrogel Harnessing the Regenerative Potential of Notochordal Cells Serves as Instructive Cell Carrier for Nucleus Pulposus Repair. Biomaterials, 328, Article ID: 123895. https://doi.org/10.1016/j.biomaterials.2025.123895
[127]
Wang, P., Yao, Y., Chen, X., Luo, W., Li, H. and Wang, D. (2025) The Role of Nucleus Pulposus Progenitor Cells in Intervertebral Disc Degeneration and Regeneration. Journal of Orthopaedic Surgery and Research, 20, Article No. 946. https://doi.org/10.1186/s13018-025-06319-5
[128]
Alexander, P.G., Yan, B., Clark, K.L., Dong, Q., Wang, D., Yang, Y., et al. (2026) Slowing Intervertebral Disc Aging in Mice through Long-Term Systemic Treatment with the Senolytic BCL-2/BCL-xL Proteolysis Targeting Chimera (PROTAC) 753b. Aging, 18, 833-853. https://doi.org/10.18632/aging.206394
[129]
Novais, E.J., Ottone, O.K., Jagannath, S., Akande, E.J., Barve, R.A. and Risbud, M.V. (2026) Dasatinib and Quercetin Senolytic Treatment Delays Early Onset Intervertebral Disc Degeneration in SM/J Mice. Bone Research, 14, Article No. 42. https://doi.org/10.1038/s41413-026-00526-4
[130]
Zhang, Y., Li, H., Chen, Y., Li, C., Ye, H., Qiu, J., et al. (2024) Nordihydroguaiaretic Acid Suppresses Ferroptosis and Mitigates Intervertebral Disc Degeneration through the NRF2/GPX4 Axis. International Immunopharmacology, 143, Article ID: 113590. https://doi.org/10.1016/j.intimp.2024.113590
[131]
Feng, C., Hu, Z., Zhao, M., Leng, C., Li, G., Yang, F., et al. (2025) Region-Specific Mitophagy in Nucleus Pulposus, Annulus Fibrosus, and Cartilage Endplate of Intervertebral Disc Degeneration: Mechanisms and Therapeutic Strategies. Frontiers in Pharmacology, 16, Article ID: 1579507. https://doi.org/10.3389/fphar.2025.1579507
[132]
Melrose, J. (2025) The Potential of Bioactive Plant Phytochemicals, Pro-Resolving Anti-Inflammatory Lipids, and Statins in the Inhibition of Intervertebral Disc Degeneration, Low Back Pain Resolution, Disc Functional Repair, and Promotion of Intervertebral Disc Regeneration. Cells, 14, Article No. 1758. https://doi.org/10.3390/cells14221758
[133]
Guo, C., Jiao, X., Du, X., Zhang, T., Peng, B. and Xu, B. (2025) Application of Self-healing Hydrogels in the Treatment of Intervertebral Disc Degeneration. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 113, e35532. https://doi.org/10.1002/jbm.b.35532
Sun, B., Lian, M., Han, Y., Mo, X., Jiang, W., Qiao, Z., et al. (2021) A 3D-Bioprinted Dual Growth Factor-Releasing Intervertebral Disc Scaffold Induces Nucleus Pulposus and Annulus Fibrosus Reconstruction. Bioactive Materials, 6, 179-190. https://doi.org/10.1016/j.bioactmat.2020.06.022
[137]
Li, F., Shi, Y., Liu, J., Yang, Y., Yan, C., Sun, X., et al. (2026) An Intelligent Nanoliposome Alleviates Disc Degeneration and Discogenic Pain by Inhibiting Neurovascular Ingrowth via a “Soil-Conditioning, Seed-Modulating, and Weeds-Suppressing” Strategy. Bioactive Materials, 58, 157-182. https://doi.org/10.1016/j.bioactmat.2025.11.048
[138]
Wang, W., Fan, C., Xu, H., Jiang, J., Liang, X., Wang, T., et al. (2026) Engineering miRNA-223 Nanocomplexes via Bioorthogonal Self-Assembly for Precision Therapy of Intervertebral Disc Degeneration. Biomaterials, 335, Article ID: 124412. https://doi.org/10.1016/j.biomaterials.2026.124412
[139]
Ryu, M., Yurube, T., Takeoka, Y., Kanda, Y., Tsujimoto, T., Miyazaki, K., et al. (2024) Gene-Silencing Therapeutic Approaches Targeting PI3K/Akt/mTOR Signaling in Degenerative Intervertebral Disk Cells: An in Vitro Comparative Study between RNA Interference and CRISPR-Cas9. Cells, 13, Article No. 2030. https://doi.org/10.3390/cells13232030
[140]
Takeoka, Y., Yurube, T. and Nishida, K. (2020) Gene Therapy Approach for Intervertebral Disc Degeneration: An Update. Neurospine, 17, 3-14. https://doi.org/10.14245/ns.2040042.021
[141]
Vijayan, V. and Lou, L. (2026) Design Principles and Mechanics: A Review of Emerging Paradigms in Intervertebral Disc Regeneration and Replacement. Macromolecular Materials and Engineering, 311, e70199. https://doi.org/10.1002/mame.70199
[142]
Ogaili, R.H., Alassal, A., Za’aba, N.F., Zulkiflee, I. and Mohd Isa, I.L. (2025) Regenerative Strategies for Intervertebral Disc Degeneration. Journal of Orthopaedic Translation, 53, 286-308. https://doi.org/10.1016/j.jot.2025.06.003
