Modern views on the pathogenesis of intervertebral disc degeneration

Introduction. Intervertebral disc (IVD) degeneration is defined as a multifactorial degenerative disease of the spine, starting from the structures of the nucleus pulposus of the IVD, spreading to the fibrous ring and other elements of the spinal motion segment. Unlike natural aging, a pathological degenerative process that occurs in IVDs as a result of the additive effect of genetic predisposition and external environmental factors leads to the formation of chronic back pain and reduces the patient’s quality of life. Despite many years of studying the problem of the pathogenesis of IVD degeneration, it is far from being resolved, which encourages us to further study the pathogenetic mechanisms of the development of this pathology.

Aim. To update the knowledge of practicing neurologists about the results of modern studies of the leading mechanisms of development of IVD degeneration in humans and their role in the development of promising biomarkers of this pathology and new strategies for pathogenetic therapy.

Materials and methods. A search and analysis of publications was carried out in Russian-language (e-Library) and Englishlanguage databases (PubMed, Oxford Press, Clinical Keys, Springer, Elsevier, Google Scholar). Search depth – 5 years (2018–2023).

Results. The analyzed and generalized results of studies of the molecular mechanisms influencing the development and progression of this pathology are presented. The leading pathogenetic mechanisms for the development of IVD degeneration, such as oxidative stress and the NO system, cytokine imbalance, increased activity of matrix metalloproteinases, dysfunction of fibrillar collagens and proteoglycan, as well as their relationship with each other, were considered.

Conclusion. The review provides a broader look at the pathogenetic mechanisms of IVD degeneration, which makes it possible to set new goals for future development of promising therapeutic strategies.

1. Tkachev A.M., Epifanov A.V., Akarachkova E.S. et al. Pathophysiological mechanisms of intervertebral disc degeneration. Russkij medicinskij zhurnal. Medicinskoe obozrenie = Russian Medical Journal. Medical Review 2019;4(2):72–7. (In Russ.).

2. Clinical recommendations. Degenerative diseases of the spine. 2021. (In Russ.). Available at: https://cr.minzdrav.gov.ru/schema/727_1

3. Pravdyuk N.G., Shostak N.A. Degenerative spine injury associated with back pain: morphogenetic aspects. Klinitsist = The Clinician 2017;11(3–4):17–22. (In Russ.). DOI: 10.17650/1818-8338-2017-11-3-4-17-22

4. Sorokin Yu.N. Back pain and intervertebral disc degeneration in the International Classification of Diseases 11th revision. Zhurnal nevrologii i psixiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry 2019;119(8):153–9. (In Russ.). DOI: 10.17116/jnevro2019119081153

5. Ashkhotov A.V., Shnayder N.A., Trefilova V.V. et al. The role of proinflammatory cytokines in the development of chronic discogenic pain syndrome. Yakutskij medicinskij zhurnal = Yakut Medical Journal 2023;84(4):128–34. (In Russ.). DOI: 10.25789/YMJ.2023.84.30

6. Trefilova V.V., Shnayder N.A., Petrova M.M. et al. Role of polymorphisms in collagen-encoding genes in intervertebral disc degeneration. Biomolecules 2021;11(9):1279. DOI: 10.3390/biom11091279

7. The World Health Organization. Available at: https://www.who.int/ru.

8. Nurgaliev Z.A., Trefilova V.V., Al-Zamil M. et al. The role of type I сollagen in intervertebral disc degeneration. Personalized Psychiatry and Neurology 2022;2(1):46–56. DOI: 10.52667/2712-91792022-2-1-46-56

9. Frapin L., Clouet J., Delplace V. et al. Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors. Adv Drug Deliv Rev 2019;149–50:49–71. DOI: 10.1016/j.addr.2019.08.007

10. Cao G., Yang S., Cao J. et al. The role of oxidative stress in intervertebral disc degeneration. Oxid Med Cell Longev 2022;12:2166817. DOI: 10.1155/2022/2166817

11. Singh A., Kukreti R., Saso L. et al. Oxidative Stress: A key modulator in neurodegenerative diseases. Molecules 2019;24(8):1583. DOI: 10.3390/molecules24081583

12. Gumanova N.G. Nitric oxide and its circulating NOx metabolites, their role in human body functioning and cardiovascular death risk prediction (part I). Profilakticheskaya meditsina = The Russian Journal of Preventive Medicine 2021;24(9):102–9. (In Russ.). DOI: 10.17116/profmed202124091102

13. Trefilova V.V., Shnayder N.A., Popova T.E. et al. The role of NO system in low back pain chronification. Personalized Psychiatry and Neurology 2021;1(1):37–45. DOI: 10.52667/2712-9179-2021-1-1-37-45

14. Lee M., Rey K., Besler K. et al. Immunobiology of nitric oxide and regulation of inducible nitric oxide synthase. Results Probl Cell Differ 2017;62:181–207. DOI: 10.1007/978-3-319-54090-0_8

15. Klimentova E.A., Suchkov I.A., Egorov A.A. et al. Apoptosis and cell proliferation markers in inflammatory fibroproliferative diseases of the vessel wall (review). Sovrem Tekhnologii Med. 2021;12(4):119–26. DOI: 10.17691/stm2020.12.4.13

16. Castania V., Issy A.C., Silveira J.W. et al. The presence of the neuronal nitric oxide synthase isoform in the intervertebral disk. Neurotox Res 2017;31(1):148–61. DOI: 10.1007/s12640-016-9676-7

17. Tao S., Shen Z., Chen J. et al. Red light-mediated photoredox catalysis triggers nitric oxide release for treatment of cutibacterium acne induced intervertebral disc degeneration. ACS Nano 2022;16(12):20376–88. DOI: 10.1021/acsnano.2c06328

18. Das U.N. Bioactive lipids in intervertebral disc degeneration and its therapeutic implications. Biosci Rep 2019;39(10):BSR20192117. DOI: 10.1042/BSR20192117

19. Rajasekaran S., Soundararajan D.C.R., Nayagam S.M. et al. Novel biomarkers of health and degeneration in human intervertebral discs: in-depth proteomic analysis of collagen framework of fetal, healthy, scoliotic, degenerate, and herniated discs. Asian Spine J 2023;17(1):17–29. DOI: 10.31616/asj.2021.0535

20. Zeldin L., Mosley G.E., Laudier D. et al. Spatial mapping of collagen content and structure in human intervertebral disk degeneration. JOR Spine 2020;3(4):e1129. DOI: 10.1002/jsp2.1129

21. Dou Y., Sun X., Ma X. et al. Intervertebral disk degeneration: the microenvironment and tissue engineering strategies. Front Bioeng Biotechnol 2021;9:592118. DOI: 10.3389/fbioe.2021.592118

22. Xie G., Liang C., Yu H. et al. Association between polymorphisms of collagen genes and susceptibility to intervertebral disc degeneration: a meta-analysis. J Orthop Surg Res 2021;16(1):616. DOI: 10.1186/s13018-021-02724-8

23. Takeoka Y., Paladugu P., Kang J.D. et al. Chondroitin sulfate proteoglycan has therapeutic potential for intervertebral disc degeneration by stimulating anabolic turnover in bovine nucleus pulposus cells under changes in hydrostatic pressure. Int J Mol Sci 2021;22(11):6015. DOI: 10.3390/ijms22116015

24. Wei Q., Zhang X., Zhou C. et al. Roles of large aggregating proteoglycans in human intervertebral disc degeneration. Connect Tissue Res 2019;60(3):209–18. DOI: 10.1080/03008207.2018.1499731

25. Harmon M.D., Ramos D.M., Nithyadevi D. et al. Growing a backbone – functional biomaterials and structures for intervertebral disc (IVD) repair and regeneration: challenges, innovations, and future directions. Biomater Sci 2020;8(5):1216–39. DOI: 10.1039/c9bm01288e

26. Liang H., Luo R., Li G. et al. The proteolysis of ECM in intervertebral disc degeneration. Int J Mol Sci 2022;23(3):1715. DOI: 10.3390/ijms23031715

27. Zhang T.W., Li Z.F., Ding W. et al. Decorin inhibits nucleus pulposus apoptosis by matrix-induced autophagy via the mTOR pathway. J Orthop Res 2021;39(8):1777–88. DOI: 10.1002/jor.24882

28. Shnayder N.A., Ashhotov A.V., Trefilova V.V. et al. Cytokine imbalance as a biomarker of intervertebral disk degeneration. Int J Mol Sci 2023;24(3):2360. DOI: 10.3390/ijms24032360

29. Shnayder N.A., Ashhotov A.V., Trefilova V.V. et al. High-tech methods of cytokine imbalance correction in intervertebral disc degeneration. Int J Mol Sci 2023;24(17):13333. DOI: 10.3390/ijms241713333

30. Guo Y., Li C., Shen B. et al. Is There any relationship between plasma IL-6 and TNF-α levels and lumbar disc degeneration? A retrospective single-center study. Dis Markers 2022;2022:6842130. DOI: 10.1155/2022/6842130

31. Xu H.W., Fang X.Y., Liu X.W. et al. α-Ketoglutaric acid ameliorates intervertebral disk degeneration by blocking the IL-6/JAK2/STAT3 pathway. Am J Physiol Cell Physiol 2023;325(4):C1119–30. DOI: 10.1152/ajpcell.00280.2023

32. Wu C., Ge J., Yang M. et al. Resveratrol protects human nucleus pulposus cells from degeneration by blocking IL-6/JAK/STAT3 pathway. Eur J Med Res 2021;26(1):81. DOI: 10.1186/s40001-021-00555-1

33. Zheng-Wei S., Yuan T., Chao-Shuai F. et al. Roles of Hippo-YAP/ TAZ signalling in intervertebral disc degeneration. Biomed Pharmacother 2023;159:114099. DOI: 10.1016/j.biopha.2022.114099

34. Ohnishi T., Iwasaki N., Sudo H. Causes of and molecular targets for the treatment of intervertebral disc degeneration: a review. Cells 2022;11(3):394. DOI: 10.3390/cells11030394

35. Chen J., Mei Z., Huang B. et al. IL-6/YAP1/β-catenin signaling is involved in intervertebral disc degeneration. J Cell Physiol 2019;234(5):5964–71. DOI: 10.1002/jcp.27065.

36. Lu K., Wang Q., Jiang H. et al. Upregulation of β-catenin signaling represents a single common pathway leading to the various phenotypes of spinal degeneration and pain. Bone Res 2023;11(1):18. DOI: 10.1038/s41413-023-00253-0

37. Du X., Liang K., Ding S. et al. Signaling mechanisms of stem cell therapy for intervertebral disc degeneration. Biomedicines 2023;11(9):2467. DOI: 10.3390/biomedicines11092467

38. Guo Z., Qiu C., Mecca C. et al. Elevated lymphotoxin-α (TNFα) is associated with intervertebral disc degeneration. BMC Musculoskelet Disord 2021;22(1):77. DOI: 10.1186/s12891-020-03934-7

39. Fischer R., Kontermann R.E., Pfizenmaier K. Selective targeting of TNF receptors as a novel therapeutic approach. Front Cell Dev Biol 2020;8:401. DOI: 10.3389/fcell.2020.00401

40. Chen D., Jiang X. Correlation between proteolytic enzymes and microangiogenesis in degenerative intervertebral disc nucleus. J Invest Surg 2021;34(6):679–84. DOI: 10.1080/08941939.2019.1679921

41. Silagi E.S., Shapiro I.M., Risbud M.V. Glycosaminoglycan synthesis in the nucleus pulposus: Dysregulation and the pathogenesis of disc degeneration. Matrix Biol 2018;71–2:368–79. DOI: 10.1016/j.matbio.2018.02.025

42. Rodionova L.V., Samoilova L.G., Sorokovikov V.A. Activity of genes of matrix metalloproteinases and their inhibitors in the ligamentum flavum of patients with stenosing processes in spinal canal and dural sac. Acta Biomedica Scientifica 2021;6(6–2): 58–72. (In Russ.). DOI: 10.29413/ABS.2021-6.6-2.7

43. Gradišnik L., Maver U., Gole B. et al. The endplate role in degenerative disc disease research: the isolation of human chondrocytes from vertebral endplate-an optimised protocol. Bioengineering (Basel) 2022;9(4):137. DOI: 10.3390/bioengineering9040137

44. Fields A.J., Ballatori A., Liebenberg E.C., Lotz J.C. Contribution of the endplates to disc degeneration. Curr Mol Biol Rep 2018;4(4):151–60. DOI: 10.1007/s40610-018-0105-y

45. Chen L., Battié M.C., Yuan Y. et al. Lumbar vertebral endplate defects on magnetic resonance images: prevalence, distribution patterns, and associations with back pain. Spine J 2020;20(3):352–60. DOI: 10.1016/j.spinee.2019.10.015

46. Velnar T., Gradisnik L. Endplate role in the degenerative disc disease: a brief review. World J Clin Case 2023;11(1):17–29. DOI: 10.12998/wjcc.v11.i1.17

47. Feng Z., Liu Y., Yang G. et al. Lumbar vertebral endplate defects on magnetic resonance images: classification, distribution patterns, and associations with modic changes and disc degeneration. Spine (Phila Pa 1976) 2018;43(13):919–27. DOI: 10.1097/BRS.0000000000002450

48. Lv B., Yuan J., Ding H. et al. Relationship between endplate defects, modic change, disc degeneration, and facet joint degeneration in patients with low back pain. Biomed Res Int 2019;2019:9369853. DOI: 10.1155/2019/9369853

49. Pfirrmann C.W., Metzdorf A., Zanetti M. et al. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 2001;26(17):1873–8. DOI: 10.1097/00007632-200109010-00011

50. Ling Z., Li L., Chen Y. et al. Changes of the end plate cartilage are associated with intervertebral disc degeneration: a quantitative magnetic resonance imaging study in rhesus monkeys and humans. J Orthop Translat 2020;24:23–31. DOI: 10.1016/j.jot.2020.04.004

51. Nehru A.P., Kanna R.M., Shetty A.P., Shanmuganathan R. Intervertebral disc degeneration and vertebral end plate damage in acute lumbar disc herniation. Indian Spine Journal 2023;6(2):118–24. DOI: 10.4103/isj.isj_11_22

52. Kurenkov E.L., Makarova V.V. Some aspects of the pathogenesis of degenerative changes in the intervertebral disc in humans. Vyatskij medicinskij vestnik = Vyatka Medical Bulletin 2018;(2):52–8. (In Russ.).