Skip to main content
Log in

Progression of lumbar spinal stenosis is influenced by polymorphism of thrombospondin 2 gene in the Korean population

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study is to determine the contribution of thrombospondin 2 (THBS2) polymorphisms to the development and progression of lumbar spinal stenosis (LSS) in the Korean population.

Methods

We studied 148 symptomatic patients with radiographically proven LSS and 157 volunteers with no history of back problems from our institution. Magnetic resonance images were obtained for all the patients and controls. Quantitative image evaluation for LSS was performed to evaluate the severity of LSS. All patients and controls were genotyped for THBS2 allele variations using a polymerase chain reaction-based technique.

Results

We found no causal single nucleotide polymorphism (SNPs) in THBS2 that were significantly associated with LSS. Two SNPs (rs6422747, rs6422748) were over-represented in controls [P = 0.042, odds ratio [OR] = 0.55 and P = 0.042, OR = 0.55, respectively]. Haplotype analysis showed that the ‘‘AGAGACG’’ haplotype (HAP4) and ‘‘AAGGACG’’ haplotype (HAP5) were over-represented in severe LSS patients (P = 0.0147, OR = 2.02 and P = 0.0137, OR = 2.48, respectively). In addition, the ‘‘AAAGGGG’’ haplotype (HAP1) was over-represented in controls (P = 0.0068, OR = 0.30).

Conclusions

Although no SNPs in THBS2 were associated with LSS, haplotypes (HAP4 and HAP5) were significantly associated with progression of LSS in the Korean population, whereas another haplotype (HAP1) may play a protective role against LSS development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

DSCSA:

Dural sac cross-sectional area

ECM:

Extracellular matrix

LRP:

Lipoprotein receptor-related protein

LSS:

Lumbar spinal stenosis

MMP:

Matrix metalloproteinase

MRI:

Magnetic resonance imaging

PCT:

Polymerase chain reaction

SNP:

Single nucleotide polymorphism

THBS:

Thrombospondin

References

  1. Agah A, Kyriakides TR, Bornstein P (2005) Proteolysis of cell-surface tissue transglutaminase by matrix metalloproteinase-2 contributes to the adhesive defect and matrix abnormalities in thrombospondin-2-null fibroblasts and mice. Am J Pathol 167:81–88

    Article  CAS  PubMed  Google Scholar 

  2. Ala-Kokko L (2002) Genetic risk factors for lumbar disc disease. Ann Med 34:42–47

    Article  CAS  PubMed  Google Scholar 

  3. Armstrong LC, Bornstein P (2003) Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol 22:63–71

    Article  CAS  PubMed  Google Scholar 

  4. Ashokkumar M, Anbarasan C, Saibabu R, Kuram S, Raman SC, Cherian KM (2011) An association study of thrombospondin 1 and 2 SNPs with coronary artery disease and myocardial infarction among South Indians. Thromb Res 128:e49–e53

    Article  CAS  PubMed  Google Scholar 

  5. Bein K, Simons M (2000) Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem 275:32167–32173

    Article  CAS  PubMed  Google Scholar 

  6. Bornstein P (1992) Thrombospondins: structure and regulation of expression. FASEB J 6:3290–3299

    CAS  PubMed  Google Scholar 

  7. Bornstein P (2001) Thrombospondins as matricellular modulators of cell function. J Clin Invest 107:929–934

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Bornstein P (2009) Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal 3:189–200

    Article  PubMed Central  PubMed  Google Scholar 

  9. Bornstein P, Agah A, Kyriakides TR (2004) The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol 36:1115–1125

    Article  CAS  PubMed  Google Scholar 

  10. Bornstein P, Sage EH (1994) Thrombospondins. Methods Enzymol 245:62–85

    CAS  PubMed  Google Scholar 

  11. Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 208:1083–1092

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927

    CAS  PubMed  Google Scholar 

  13. Gruber HE, Ingram JA, Hanley EN Jr (2006) Immunolocalization of thrombospondin in the human and sand rat intervertebral disc. Spine (Phila Pa 1976) 31:2556–2561

    Article  Google Scholar 

  14. Hahn-Dantona E, Ruiz JF, Bornstein P, Strickland DK (2001) The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. J Biol Chem 276:15498–15503

    Article  CAS  PubMed  Google Scholar 

  15. Hirose Y, Chiba K, Karasugi T, Nakajima M, Kawaguchi Y, Mikami Y, Furuichi T, Mio F, Miyake A, Miyamoto T, Ozaki K, Takahashi A, Mizuta H, Kubo T, Kimura T, Tanaka T, Toyama Y, Ikegawa S (2008) A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am J Hum Genet 82:1122–1129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hyun SJ, Park BG, Rhim SC, Bae CW, Lee JK, Roh SW, Jeon SR (2011) A haplotype at the COL9A2 gene locus contributes to the genetic risk for lumbar spinal stenosis in the Korean population. Spine (Phila Pa 1976) 36:1273–1278

    Article  Google Scholar 

  17. Koga H, Sakou T, Taketomi E, Hayashi K, Numasawa T, Harata S, Yone K, Matsunaga S, Otterud B, Inoue I, Leppert M (1998) Genetic mapping of ossification of the posterior longitudinal ligament of the spine. Am J Hum Genet 62:1460–1467

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Kyriakides TR, Zhu YH, Smith LT, Bain SD, Yang Z, Lin MT, Danielson KG, Iozzo RV, LaMarca M, McKinney CE, Ginns EI, Bornstein P (1998) Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol 140:419–430

    Article  CAS  PubMed  Google Scholar 

  19. Maeda S, Ishidou Y, Koga H, Taketomi E, Ikari K, Komiya S, Takeda J, Sakou T, Inoue I (2001) Functional impact of human collagen alpha2(XI) gene polymorphism in pathogenesis of ossification of the posterior longitudinal ligament of the spine. J Bone Miner Res 16:948–957

    Article  CAS  PubMed  Google Scholar 

  20. Nakao T, Kurita N, Komatsu M, Yoshikawa K, Iwata T, Utsunomiya T, Shimada M (2011) Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer. Int J Clin Oncol 16:145–152

    Article  CAS  PubMed  Google Scholar 

  21. Noponen-Hietala N, Kyllonen E, Mannikko M, Ilkko E, Karppinen J, Ott J, Ala-Kokko L (2003) Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 62:1208–1214

    Article  CAS  PubMed  Google Scholar 

  22. Punekar S, Zak S, Kalter VG, Dobransky L, Punekar I, Lawler JW, Gutierrez LS (2008) Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease. Pathobiology 75:9–21

    Article  CAS  PubMed  Google Scholar 

  23. Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, Tsunoda T, Kamata M, Kubo T, Toyama Y, Kimura T, Nakamura Y, Ikegawa S (2005) A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet 37:607–612

    Article  CAS  PubMed  Google Scholar 

  24. Sheehan JM, Shaffrey CI, Jane JA Sr (2001) Degenerative lumbar stenosis: the neurosurgical perspective. Clin Orthop Relat Res 384:61–74

    Article  PubMed  Google Scholar 

  25. Sirvanci M, Bhatia M, Ganiyusufoglu KA, Duran C, Tezer M, Ozturk C, Aydogan M, Hamzaoglu A (2008) Degenerative lumbar spinal stenosis: correlation with Oswestry disability index and MR imaging. Eur Spine J 17:679–685

    Article  PubMed Central  PubMed  Google Scholar 

  26. Spivak JM (1998) Degenerative lumbar spinal stenosis. J Bone Jt Surg Am 80:1053–1066

    CAS  Google Scholar 

  27. Vallejo AN, Mugge LO, Klimiuk PA, Weyand CM, Goronzy JJ (2000) Central role of thrombospondin-1 in the activation and clonal expansion of inflammatory T cells. J Immunol 164:2947–2954

    CAS  PubMed  Google Scholar 

  28. Vallejo AN, Yang H, Klimiuk PA, Weyand CM, Goronzy JJ (2003) Synoviocyte-mediated expansion of inflammatory T cells in rheumatoid synovitis is dependent on CD47-thrombospondin 1 interaction. J Immunol 171:1732–1740

    CAS  PubMed  Google Scholar 

  29. Wynne-Davies R, Walsh WK, Gormley J (1981) Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis. J Bone Jt Surg Br 63B:508–515

    CAS  Google Scholar 

  30. Yang Z, Kyriakides TR, Bornstein P (2000) Matricellular proteins as modulators of cell-matrix interactions: adhesive defect in thrombospondin 2-null fibroblasts is a consequence of increased levels of matrix metalloproteinase-2. Mol Biol Cell 11:3353–3364

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Yang Z, Strickland DK, Bornstein P (2001) Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem 276:8403–8408

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The manuscript submitted does not contain information about medical device(s)/drug(s). This study was supported by a Grant (2010-204) from the Asan Institute for Life Sciences, Seoul, Republic of Korea.

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Seung-Chul Rhim.

Additional information

S.-J. Hyun and B. G. Park equally contributed to the work as a co-first author.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hyun, SJ., Park, B.G., Rhim, SC. et al. Progression of lumbar spinal stenosis is influenced by polymorphism of thrombospondin 2 gene in the Korean population. Eur Spine J 23, 57–63 (2014). https://doi.org/10.1007/s00586-013-2866-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-013-2866-6

Keywords

Navigation