Single nucleotide polymorphisms of intervertebral disc collagens and prospects for their correction




intervertebral disc, collagen type I, collagen type II, collagen type IX, collagen type XI


The main functions of the intervertebral disc (IVD) are ensured by the reliable integration of three structures of the IVD: the annulus fibrosus (AF), the hydrated nucleus pulposus (NP) and the two cartilaginous end plates (CEP). All molecular components are involved in the integration of the three anatomical structures of the IVD, however, the most important biomechanical properties - resistance to rupture / stretching / shift, resistance to static axial loads are mostly determined by collagens.
The unique properties of collagens depend on the amino acid sequence of the three alpha (α) chains, which, after spiralization and condensation, form the collagen molecule - tropocollagen. The amino acid sequence contains all the necessary information for spiralization, modification, secretion of tropocollagen, its processing, condensation into fibrils and fibers according to the self-assembly principle. Changes in the primary amino acid sequence, depending on the substitution itself and its localization, lead to disruption of the stages of tropocollagen formation, its extracellular processing, and condensation.
Currently, most of the research is devoted to the study of polymorphisms in the genes of IVD collagen types I, II, IX and XI. Algorithms for using information about genetic polymorphisms of collagen genes are only being formed. Data on genetic variation are often conflicting. An important aspect is the homogeneity of the study group by age, ethnicity, gender, as well as by the type of degenerative changes. There is also insufficient data on the effect of polymorphism on the properties of the collagen molecule, which greatly complicates the creation of standards for therapeutic correction.
This literature review is devoted to the consideration of new data on collagen genes polymorphisms, the impact of these polymorphisms on integrative relationships in IVD structures, as well as the prospects for the correction of genetic abnormalities.

Author Biographies

Eugene G. Pedachenko, Romodanov Neurosurgery Institute, Kyiv

Department of Miniinvasive and Laser Spinal Neurosurgery

Iryna.G. Vasilyeva, Romodanov Neurosurgery Institute, Kyiv

Department of Neurobiochemistry


Kirnaz S, Capadona C, Lintz M, Kim B, Yerden R, Goldberg JL, Medary B, Sommer F, McGrath LB Jr, Bonassar LJ, Härtl R. Pathomechanism and Biomechanics of Degenerative Disc Disease: Features of Healthy and Degenerated Discs. Int J Spine Surg. 2021 Apr;15(s1):10-25. doi: 10.14444/8052

Fontes RBV, Baptista JS, Rabbani SR, Traynelis VC, Liberti EA. Normal aging in human lumbar discs: An ultrastructural comparison. PLoS One. 2019 Jun 20;14(6):e0218121. doi: 10.1371/journal.pone.0218121

Fearing BV, Hernandez PA, Setton LA, Chahine NO. Mechanotransduction and cell biomechanics of the intervertebral disc. JOR Spine. 2018 Sep;1(3):e1026. doi: 10.1002/jsp2.1026

Tam V, Chen P, Yee A, Solis N, Klein T, Kudelko M, Sharma R, Chan WC, Overall CM, Haglund L, Sham PC, Cheah KSE, Chan D. DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics. Elife. 2020 Dec 31;9:e64940. doi: 10.7554/eLife.64940

Lamandé SR, Bateman JF. Genetic Disorders of the Extracellular Matrix. Anat Rec (Hoboken). 2020 Jun;303(6):1527-1542. doi: 10.1002/ar.24086

Kadler KE. Fell Muir Lecture: Collagen fibril formation in vitro and in vivo. Int J Exp Pathol. 2017 Feb;98(1):4-16. doi: 10.1111/iep.12224

Barnes AM, Ashok A, Makareeva EN, Brusel M, Cabral WA, Weis M, Moali C, Bettler E, Eyre DR, Cassella JP, Leikin S, Hulmes DJS, Kessler E, Marini JC. COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing. Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2210-2223. doi: 10.1016/j.bbadis.2019.04.018

Oichi T, Taniguchi Y, Oshima Y, Tanaka S, Saito T. Pathomechanism of intervertebral disc degeneration. JOR Spine. 2020 Feb 13;3(1):e1076. doi: 10.1002/jsp2.1076

Chakkalakal SA, Heilig J, Baumann U, Paulsson M, Zaucke F. Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival. Int J Mol Sci. 2018 Feb 11;19(2):541. doi: 10.3390/ijms19020541

Wu M, Cronin K, Crane JS. Biochemistry, Collagen Synthesis. 2021 Sep 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.

San Antonio JD, Jacenko O, Fertala A, Orgel JPRO. Collagen Structure-Function Mapping Informs Applications for Regenerative Medicine. Bioengineering (Basel). 2020 Dec 29;8(1):3. doi: 10.3390/bioengineering8010003

Sharma U, Carrique L, Vadon-Le Goff S, Mariano N, Georges RN, Delolme F, Koivunen P, Myllyharju J, Moali C, Aghajari N, Hulmes DJ. Structural basis of homo- and heterotrimerization of collagen I. Nat Commun. 2017 Mar 10;8:14671. doi: 10.1038/ncomms14671

DiChiara AS, Li RC, Suen PH, Hosseini AS, Taylor RJ, Weickhardt AF, Malhotra D, McCaslin DR, Shoulders MD. A cysteine-based molecular code informs collagen C-propeptide assembly. Nat Commun. 2018 Oct 11;9(1):4206. doi: 10.1038/s41467-018-06185-2

Zheng H, Lu C, Lan J, Fan S, Nanda V, Xu F. How electrostatic networks modulate specificity and stability of collagen. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6207-6212. doi: 10.1073/pnas.1802171115. Erratum in: Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6098

Han S, McBride DJ, Losert W, Leikin S. Segregation of type I collagen homo- and heterotrimers in fibrils. J Mol Biol. 2008 Oct 31;383(1):122-32. doi: 10.1016/j.jmb.2008.08.008

Tian C, Huang Y, Clauser KR, Rickelt S, Lau AN, Carr SA, Vander Heiden MG, Hynes RO. Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells. Nat Commun. 2021 Apr 20;12(1):2328. doi: 10.1038/s41467-021-22490-9

Zhong B, Huang D, Ma K, Deng X, Shi D, Wu F, Shao Z. Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis. Oncotarget. 2017 Sep 8;8(43):75488-75499. doi: 10.18632/oncotarget.20797

Tilkeridis C, Bei T, Garantziotis S, Stratakis CA. Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits. J Med Genet. 2005 Jul;42(7):e44. doi: 10.1136/jmg.2005.033225

Pluijm SM, van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P. Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis. 2004 Jan;63(1):71-7. doi: 10.1136/ard.2002.002287

Videman T, Saarela J, Kaprio J, Näkki A, Levälahti E, Gill K, Peltonen L, Battié MC. Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum. 2009 Feb;60(2):470-81. doi: 10.1002/art.24268

Torre OM, Mroz V, Bartelstein MK, Huang AH, Iatridis JC. Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies. Ann N Y Acad Sci. 2019 Apr;1442(1):61-78. doi: 10.1111/nyas.13964

Deng Y, Tan XT, Wu Q, Wang X. Correlations Between COL2A and Aggrecan Genetic Polymorphisms and the Risk and Clinicopathological Features of Intervertebral Disc Degeneration in a Chinese Han Population: A Case-Control Study. Genet Test Mol Biomarkers. 2017 Feb;21(2):108-115. doi: 10.1089/gtmb.2016.0256

Li YZ, Li J, Zhang J, Lin Q. Association of COL2A and Aggrecan polymorphisms with the susceptibility of intervertebral disc degeneration. Int J Clin Exp Med. 2016 Jan 1;9(2):3885-92. Available at:

Teles Filho RV, Abe GM, Daher MT. Genetic Influence in Disc Degeneration - Systematic Review of Literature. Rev Bras Ortop (Sao Paulo). 2020 Apr;55(2):131-138. doi: 10.1055/s-0039-1692626

Mayer JE, Iatridis JC, Chan D, Qureshi SA, Gottesman O, Hecht AC. Genetic polymorphisms associated with intervertebral disc degeneration. Spine J. 2013 Mar;13(3):299-317. doi: 10.1016/j.spinee.2013.01.041

Aladin DM, Cheung KM, Chan D, Yee AF, Jim JJ, Luk KD, Lu WW. Expression of the Trp2 allele of COL9A2 is associated with alterations in the mechanical properties of human intervertebral discs. Spine (Phila Pa 1976). 2007 Dec 1;32(25):2820-6. doi: 10.1097/BRS.0b013e31815b75c5

Kawaguchi Y. Genetic background of degenerative disc disease in the lumbar spine. Spine Surg Relat Res. 2018 Feb 28;2(2):98-112. doi: 10.22603/ssrr.2017-0007

Higashino K, Matsui Y, Yagi S, Takata Y, Goto T, Sakai T, Katoh S, Yasui N. The alpha2 type IX collagen tryptophan polymorphism is associated with the severity of disc degeneration in younger patients with herniated nucleus pulposus of the lumbar spine. Int Orthop. 2007 Feb;31(1):107-11. doi: 10.1007/s00264-006-0117-8

Seki S, Kawaguchi Y, Mori M, Mio F, Chiba K, Mikami Y, Tsunoda T, Kubo T, Toyama Y, Kimura T, Ikegawa S. Association study of COL9A2 with lumbar disc disease in the Japanese population. J Hum Genet. 2006;51(12):1063-1067. doi: 10.1007/s10038-006-0062-9

Zhang Z, Zhang J, Ding L, Teng X. Meta-analysis of the association between COL9A2 genetic polymorphisms and lumbar disc disease susceptibility. Spine (Phila Pa 1976). 2014 Sep 15;39(20):1699-706. doi: 10.1097/BRS.0000000000000497

Fiani B, Covarrubias C, Jarrah R. Genetic Predictors of Early-Onset Spinal Intervertebral Disc Degeneration: Part One of Two. Cureus. 2021 May 22;13(5):e15182. doi: 10.7759/cureus.15182

Bagheri MH, Honarpisheh AP, Yavarian M, Alavi Z, Siegelman J, Valtchinov VI. MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males. Spine (Phila Pa 1976). 2016 Nov 1;41(21):1661-1667. doi: 10.1097/BRS.0000000000001617

Toktaş ZO, Ekşi MŞ, Yılmaz B, Demir MK, Özgen S, Kılıç T, Konya D. Association of collagen I, IX and vitamin D receptor gene polymorphisms with radiological severity of intervertebral disc degeneration in Southern European Ancestor. Eur Spine J. 2015 Nov;24(11):2432-41. doi: 10.1007/s00586-015-4206-5

Rathod TN, Chandanwale AS, Gujrathi S, Patil V, Chavan SA, Shah MN. Association between single nucleotide polymorphism in collagen IX and intervertebral disc disease in the Indian population. Indian J Orthop. 2012 Jul;46(4):420-6. doi: 10.4103/0019-5413.97261

Wu H, Wang S, Chen W, Zhan X, Xiao Z, Jiang H, Wei Q. Collagen IX gene polymorphisms and lumbar disc degeneration: a systematic review and meta-analysis. J Orthop Surg Res. 2018 Mar 5;13(1):47. doi: 10.1186/s13018-018-0750-0

Martirosyan NL, Patel AA, Carotenuto A, Kalani MY, Belykh E, Walker CT, Preul MC, Theodore N. Genetic Alterations in Intervertebral Disc Disease. Front Surg. 2016 Nov 21;3:59. doi: 10.3389/fsurg.2016.00059

Tang X, Jing L, Richardson WJ, Isaacs RE, Fitch RD, Brown CR, Erickson MM, Setton LA, Chen J. Identifying molecular phenotype of nucleus pulposus cells in human intervertebral disc with aging and degeneration. J Orthop Res. 2016 Aug;34(8):1316-26. doi: 10.1002/jor.23244

Mio F, Chiba K, Hirose Y, Kawaguchi Y, Mikami Y, Oya T, Mori M, Kamata M, Matsumoto M, Ozaki K, Tanaka T, Takahashi A, Kubo T, Kimura T, Toyama Y, Ikegawa S. A functional polymorphism in COL11A1, which encodes the alpha 1 chain of type XI collagen, is associated with susceptibility to lumbar disc herniation. Am J Hum Genet. 2007 Dec;81(6):1271-7. doi: 10.1086/522377

Liu W, Sun G, Guo L, Wang L, Fan W, Lang M, Chen D, Yi X. A genetic variant in COL11A1 is functionally associated with lumbar disc herniation in Chinese population. J Genet. 2017 Dec;96(6):867-872. doi: 10.1007/s12041-017-0874-8

Koyama K, Nakazato K, Maeda S, Kikuchi N, Matsumoto S, Hiranuma K. Association of COL11A1 4603C/T polymorphism with cervical disc degeneration in collegiate wrestlers. J Sports Med Phys Fitness. 2018 Nov;58(11):1695-1700. doi: 10.23736/S0022-4707.17.07724-6

Wu F, Huang X, Zhang Z, Shao Z. A Meta-analysis Assessing the Association Between COL11A1 and GDF5 Genetic Variants and Intervertebral Disc Degeneration Susceptibility. Spine (Phila Pa 1976). 2020 Jun 1;45(11):E616-E623. doi: 10.1097/BRS.0000000000003371

Jiang H, Yang Q, Jiang J, Zhan X, Xiao Z. Association between COL11A1 (rs1337185) and ADAMTS5 (rs162509) gene polymorphisms and lumbar spine pathologies in Chinese Han population: an observational study. BMJ Open. 2017 Jun 4;7(5):e015644. doi: 10.1136/bmjopen-2016-015644

Solovieva S, Lohiniva J, Leino-Arjas P, Raininko R, Luoma K, Ala-Kokko L, Riihimäki H. Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J. 2006 May;15(5):613-9. doi: 10.1007/s00586-005-0988-1

Yang X, Jia H, Xing W, Li F, Li M, Sun K, Zhu Y. Genetic variants in COL11A2 of lumbar disk degeneration among Chinese Han population. Mol Genet Genomic Med. 2019 Feb;7(2):e00524. doi: 10.1002/mgg3.524

Li X, Wang F, Lan Y, Bian R, Wang Y, Zhang X, Guo Y, Xiao L, Ni W, Zhao X, Luo G, Zhan R. GDF-5 induces epidermal stem cell migration via RhoA-MMP9 signalling. J Cell Mol Med. 2021 Feb;25(4):1939-1948. doi: 10.1111/jcmm.15925

Krut Z, Pelled G, Gazit D, Gazit Z. Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells. 2021 Aug 29;10(9):2241. doi: 10.3390/cells10092241

Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021 Feb 12;14(1):24. doi: 10.1186/s13045-021-01037-x

Kumar H, Ha DH, Lee EJ, Park JH, Shim JH, Ahn TK, Kim KT, Ropper AE, Sohn S, Kim CH, Thakor DK, Lee SH, Han IB. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther. 2017 Nov 15;8(1):262. doi: 10.1186/s13287-017-0710-3

Atluri S, Murphy MB, Dragella R, Herrera J, Boachie-Adjei K, Bhati S, Manocha V, Boddu N, Yerramsetty P, Syed Z, Ganjam M, Jain D, Syed Z, Grandhi N, Manchikanti L. Evaluation of the Effectiveness of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Chronic Low Back Pain Due to Severe Lumbar Spinal Degeneration: A 12-Month, Open-Label, Prospective Controlled Trial. Pain Physician. 2022 Mar;25(2):193-207

Xuan A, Ruan D, Wang C, He Q, Wang D, Hou L, Zhang C, Li C, Ji W, Wen T, Xu C, Zhu Z. Intradiscal Injection of Autologous Discogenic Cells in Patients with Discectomy: A Prospective Clinical Study of Its Safety and Feasibility. Stem Cells Transl Med. 2022 May 27;11(5):490-503. doi: 10.1093/stcltm/szac013

Wei A, Tao H, Chung SA, Brisby H, Ma DD, Diwan AD. The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discs. J Orthop Res. 2009 Mar;27(3):374-9. doi: 10.1002/jor.20567

Zhou X, Zhang F, Wang D, Wang J, Wang C, Xia K, Ying L, Huang X, Tao Y, Chen S, Xue D, Hua J, Liang C, Chen Q, Li F. Micro Fragmented Adipose Tissue Promotes the Matrix Synthesis Function of Nucleus Pulposus Cells and Regenerates Degenerated Intervertebral Disc in a Pig Model. Cell Transplant. 2020 Jan-Dec;29:963689720905798. doi: 10.1177/0963689720905798

Ma C, Wang R, Zhao D, Wang N, Han Y, Wang S, Gao T, Wang B, Lu L. Efficacy of Platelet-Rich Plasma Containing Xenogenic Adipose Tissue-Derived Stromal Cells on Restoring Intervertebral Disc Degeneration: A Preclinical Study in a Rabbit Model. Pain Res Manag. 2019 Apr 16;2019:6372356. doi: 10.1155/2019/6372356

Noriega DC, Ardura F, Hernández-Ramajo R, Martín-Ferrero MÁ, Sánchez-Lite I, Toribio B, Alberca M, García V, Moraleda JM, Sánchez A, García-Sancho J. Intervertebral Disc Repair by Allogeneic Mesenchymal Bone Marrow Cells: A Randomized Controlled Trial. Transplantation. 2017 Aug;101(8):1945-1951. doi: 10.1097/TP.0000000000001484

Purmessur D, Schek RM, Abbott RD, Ballif BA, Godburn KE, Iatridis JC. Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells. Arthritis Res Ther. 2011 May 31;13(3):R81. doi: 10.1186/ar3344



How to Cite

Pedachenko, E. G. ., & Vasilyeva, I. (2022). Single nucleotide polymorphisms of intervertebral disc collagens and prospects for their correction. Ukrainian Neurosurgical Journal, 28(4), 13–18.



Review articles