Journal of Occupational Rehabilitation

, Volume 24, Issue 2, pp 370–381 | Cite as

Matrix Metalloproteinase-3, Vitamin D Receptor Gene Polymorphisms, and Occupational Risk Factors in Lumbar Disc Degeneration

  • N. H. Zawilla
  • H. Darweesh
  • N. Mansour
  • S. Helal
  • F. M. Taha
  • M. Awadallah
  • R. El Shazly


Background Lumbar disc degeneration (LDD) is a process that begins early in life, contributing to the development of low back pain. LDD is a consequence of a variety of factors, and its etiology remains poorly understood. Objectives to investigate occupational and genetic risk factors inducing lumbar disc degeneration, and to evaluate the possible association of genetic polymorphisms of matrix metalloproteinase 3 (MMP-3) and vitamin D receptor (VDR) with the severity of LDD in an Egyptian population. Subjects and Methods A case control study involving 84 LDD and 60 controls was carried out. Five types of work related factors were investigated by questionnaire, complete neurological examination for all subjects and MRI for the cases. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect polymorphisms in MMP-3 Promoter (−1,171 6A/5A) (rs 731236) and VDR-Apa (rs 35068180). Results We found that family history, back injury, smoking, high level of sitting, bending/twisting, physical workload, lifting, whole body vibration, mutant allele 5A of MMP-3 and mutant allele T of VDR were significantly associated with LDD (OR = 2.9, 3.1, 2.1, 11.1, 15.9, 11.7, 8.2, 12.6, 2.5 and 3.1 respectively, p < 0.05). Cases that carry allele 5A and/or allele T were associated with LDD severity. Conclusion LDD is closely associated in occurrence and severity with occupational, environmental risk factors and susceptibility genes namely MMP-3, and VDR (ApaI). This study throws light on the importance of screening for early detection of susceptible individuals and disease prevention.


Lumbar disc degeneration Occupational risk factors MMP3 VDR 


  1. 1.
    Taher F, Essig DR, Lebl DR, Hughes AP, Sama AA, Cammisa FP, Girardi FP. Lumbar degenerative disc disease: current and future concepts of diagnosis and management. Adv Orthop. 2012;. doi:10.1155/2012/970752.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Freemont AJ. The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology. 2009;48:5–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Yaun HY, Tang Y, Liang Y, Lei L, Xiao G, Wang S, Xia Z. Matrix metalloproteinase-3 and vitamin D receptor genetic polymorphism, and their interaction with occupational exposure in lumbar disc degeneration. J Occup Health. 2010;52:23–30.CrossRefGoogle Scholar
  4. 4.
    Williams F, Sambrook P. Neck and back pain and intervertebral disc degeneration: role of occupational factors. Best Pract Res. 2011;25(1):69–79.CrossRefGoogle Scholar
  5. 5.
    Kalichman L, Hunter DJ. The genetics of intervertebral disc degeneration associated genes. Joint Bone Spine. 2008;75(4):388–96.PubMedCrossRefGoogle Scholar
  6. 6.
    Gallieni M, Cozzolino M, Fallabrino G, Pasho S, Olivi L, Brancaccio D, et al. Physiology and pathophysiology. Int J Artif Organs. 2009;32:87–94.PubMedGoogle Scholar
  7. 7.
    Michaelsson K, Wolk A, Jacobsson A, Kindmark A, Grundberg E, Stiger F, Mallmin H, et al. The positive effect of dietary vitamin D intake on bone mineral density in men is modulated by the polyadenosine repeat polymorphism of the vitamin D receptor. Bone. 2006;39:1343–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Colombini A, Cauci S, Lombardi G, Lanteri P, Croiset S, Brayda-Bruno M, Banfi G. Relationship between vitamin D receptor gene (VDR) polymorphisms, vitamin D status, osteoarthritis and intervertebral disc degeneration (Review). J Steroid Biochem Mol Biol. 2013;138:24–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367:284–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H, Pols HA. Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states. J Steroid Biochem Mol Biol. 2004;89:187–93.PubMedCrossRefGoogle Scholar
  11. 11.
    Ogunkolade BW, Boucher BJ, Prahl JM, Bustin SA, Burrin JM, Noonan K, North BV, et al. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes. 2002;51:2294–300.PubMedCrossRefGoogle Scholar
  12. 12.
    Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta. 2006;371:1–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Priestley L, Fergusson C, Ogilvie D, Wordsworth P, Smith R, Pattrick M, Doherty M, Sykes B. A limited association of generalized osteoarthritis with alleles at the type II collagen locus: cOL2A1. Br J Rheumatol. 1991;30(4):272–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Takahashi M, Haro H, Wakabayashi Y, Kawa-uchi T, Komori H, Shinomiya K. The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene. J Bone Joint Surg (Br). 2001;83-B: 491–5.Google Scholar
  15. 15.
    Omair A, Holden M, Alexandra ML, Olav Reikeras O, Brox JI. Treatment outcome of chronic low back pain and radiographic lumbar disc degeneration are associated with inflammatory and matrix degrading gene variants: a prospective genetic association study. BMC Musculoskelet Disord. 2013;14:105.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. Revised by the 52nd WMA General Assembly, Edinburgh, Scotland. October 2000.
  17. 17.
    Wiktorin C, Hjelm EW, Winkel J, Köster M. Reproducibility of a questionnaire for assessment of physical load during work and leisure time. Stockholm MUSIC 1 study group. MUSculoskeletal Intervention Center. J Occup Environm Med. 1996;38:190–201.Google Scholar
  18. 18.
    NIOSH. National Institute of Occupational Safety and Health. National Occupational Research agenda for musculoskeletal disorders, DHHS (NIOSH) publications No. 2001-117-Cincinnati: DHHS, NIOSH; 2001.Google Scholar
  19. 19.
    Devillé WL, van der Windt DA, Dzaferagić A, Bezemer PD, Bouter LM. The test of Lasègue: systematic review of the accuracy in diagnosing herniated discs. Spine. 2000;25(9):1140–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Kettler A, Wilke HJ. Review of existing grading systems for cervical or lumbar disc and facet joint degeneration. Eur Spine J. 2006;15(6):705–18.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Vairaktaris E, Yapijakis C, Vasiliou S, Derka S, Nkenke E, Serefoglou Z, et al. Association of −1171 promoter polymorphism of matrix metalloproteinase-3 with increased risk for oral cancer. Anticancer Res. 2007;27(6B):4095–100.Google Scholar
  22. 22.
    Carless MA, Kraska T, Lintell N, Neale RE, Green AC, Griffiths LR. Polymorphisms of the VDR gene are associated with presence of solar keratoses on the skin. Br J Dermatol. 2008;159(4):804–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Seidler A, Bolm-Audorff U, Siol T, Henkel N, Fuchs C, Schug C, et al. Occupational risk factors for symptomatic lumbar disc herniation; a case-control study. Occup Environ Med. 2003;60:821–30.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Seidler A, Bergmann A, Jäger M, Ellegast W, et al. Cumulative occupational lumbar load and lumbar disc disease—results of a German multi-center case-control study (EPILIFT). BMC Musculoskelet Disord. 2009;10:48. doi:10.1186/1471-2474-10-48.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Adams MA, McNally DS, Dolan P. Stress distributions inside intervertebral discs. The effects of age and degeneration. J Bone Joint Surg Br. 1996;78:965–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Iatridis JC, Mente PL, Stokes IA, Aronsson DD, Alini M. Compression- induced changes in intervertebral disc properties in a rat tail model. Spine. 1999;24:996–1002.PubMedCrossRefGoogle Scholar
  27. 27.
    Keller TS, Hansson TH, Holm S, Pope MH, Spengler DM. In vivo creep behavior of the normal and degenerated porcine intervertebral disc: a preliminary report. J Spinal Disord. 1988;1:267–78.PubMedGoogle Scholar
  28. 28.
    Hadjipavlou AG, Tzermiadianos MN, Bogduk N, et al. The pathophysiology of disc degeneration: a critical review. J Bone Joint Surg Br. 2008;90:1261.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang Y, Zhang F, Sun Z, Guo W, Liu J, Liu M, Guoy X. A controlled case study of the relationship between environmental risk factors and apoptotic gene polymorphism and lumbar disc herniation. Am J Pathol. 2013;182:56–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Mohammed A, Anil K, Bobby Y, Abhinav S, Mike W, Allen G. Effect of nicotine on spinal disc cells: a cellular mechanism for disc degeneration. Spine. 2004;29:568–75.CrossRefGoogle Scholar
  31. 31.
    Battie MC, Videman T, Gill K, Moneta A, Giovannil B, Nyman R, Kaprio J, Koskenvuo M. Volvo award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins. Spine. 1991;16:1015–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Oda H, Matsuzaki Y, Wakabayash K, Uematsu Y, Iwashi M. Degeneration of intervertebral discs due to smoking: experimental assessment in a rat- smoking model. J Orthop Sci. 2004;9:135–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Nunes FT, Conforti-Froes ND, Negrelli WF, Souza DRS. Genetic and environmental factors involved in intervertebral disc degeneration. Acta Ortop Bras. 2007;15(1):9–13.Google Scholar
  34. 34.
    Varlotta GP, Brown MD, Kelsey JI, Golden AL. Familial predisposition for herniation of a lumbar disc in patients who are less than twenty one years old. J Bone Joint Surg (Am). 1991;73:124–8.Google Scholar
  35. 35.
    Riihimaki H, Viikari-Juntura E, Moneta G, Kuha J, Videman T, Tola S. Incidence of sciatic pain among men in machine operating, dynamic physical work, and sedentary work: a three-year follow-up. Spine. 1994;19(2):138–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Weiler C, Nerlich AG, Zipperer J, Bachmeier BE, Boos N. SSE award competition in basic science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J. 2002;11(4):308–20.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Ye S, Eriksson P, Hamsten A, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996;271:13055–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Bijerk C, Houwing-Duistermaat JJ, Valkenberg HA. Heritability of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine. Arthritis Rheum. 1999;42:1729–35.CrossRefGoogle Scholar
  39. 39.
    Terashima M, Akita H, Kanazawa K, et al. Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction. Circulation. 1999;99:2717–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Colombini A, Lanteri P, Lombardi G, Grasso D, Recordati C, Lovi A, Banfi G, et al. Metabolic effects of vitamin D active metabolites in monolayer and micromass cultures of nucleus pulposus and annulus fibrosus cells isolated from human intervertebral disc. Int J Biochem Cell Biol. 2012;44(6):1019–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Videman T, Leppavuori J, Kaprio J. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine. 1998;23:2477–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Balmain N, Hauchecorne M, Pike JW, Cuisinier-Gleizes P, Mathieu H. Distribution and subcellular immunolocalization of 1, 25-dihydroxyvitamin D3 receptors in rat epiphyseal cartilage. Cell Mol Biol (Noisy-le-grand).1993;39:339–50.Google Scholar
  43. 43.
    Gruber HE, Hoelscher G, Ingram JA, Chow Y, Loeffle B, Hanley EN. 1,25(OH)2-vitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine 2008;33(7):755–65.Google Scholar
  44. 44.
    Wang ZC, Chen XS, Wang DW, Shi JG, Jia LS, Xu GH. The genetic association of vitamin D receptor polymorphisms and cervical spondylotic myelopathy in Chinese subjects. Clin Chim Acta. 2010;411:794–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Pockert AJ, Richardson SM, Le Maitre CL, Lyon M, Deakin JA, et al. Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum. 2009;60(2):482–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Maksymowych WP, Landewe R, Conner-Spady B, Dougados M, Mielants H, van der Tempel H, Poole AR, et al. Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis. Arthritis Rheum. 2007;56(6):1846–53.PubMedCrossRefGoogle Scholar
  47. 47.
    Valdes AM, Hassett G, Hart D, Spector T. Radiographic progression of lumbar spine disc degeneration is influenced by variation at inflammatory genes: a candidate SNP association study in the chingford cohort. Spine. 2005;30:2445–51.PubMedCrossRefGoogle Scholar
  48. 48.
    Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T. The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am. 2002;84A:2022–8.Google Scholar
  49. 49.
    Lee Y, Woo J, Choi S, Ji J, Song G. Vitamin D receptor TaqI, BsmI and ApaI polymorphisms and osteoarthritis susceptibility: a meta-analysis. Joint Bone Spine. 2009;76:156–61.PubMedCrossRefGoogle Scholar
  50. 50.
    Lorentzon M, Lorentzon R, Nordström P.Vitamin D receptor gene polymorphism is related to bone density, circulating osteocalcin, and parathyroid hormone in healthy adolescent girls. Bone Miner Metab. 2001;19:302–7.Google Scholar
  51. 51.
    Kepler CK, Ponnappan RK, Tannoury CA, Risbud MV, Anderson DG. The molecular basis of intervertebral disc degeneration. Spine. 2013;13(3):318–30.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • N. H. Zawilla
    • 1
  • H. Darweesh
    • 2
  • N. Mansour
    • 1
  • S. Helal
    • 1
  • F. M. Taha
    • 3
  • M. Awadallah
    • 4
  • R. El Shazly
    • 2
  1. 1.Occupational and Environmental Medicine Department, Faculty of MedicineCairo UniversityGizaEgypt
  2. 2.Rheumatology and Rehabilitation Department, Faculty of MedicineCairo UniversityGizaEgypt
  3. 3.Medical Biochemistry Department, Faculty of MedicineCairo UniversityGizaEgypt
  4. 4.Radiology Department, Faculty of MedicineCairo UniversityGizaEgypt

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