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.
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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
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
Ala-Kokko L (2002) Genetic risk factors for lumbar disc disease. Ann Med 34:42–47
Armstrong LC, Bornstein P (2003) Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol 22:63–71
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
Bein K, Simons M (2000) Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem 275:32167–32173
Bornstein P (1992) Thrombospondins: structure and regulation of expression. FASEB J 6:3290–3299
Bornstein P (2001) Thrombospondins as matricellular modulators of cell function. J Clin Invest 107:929–934
Bornstein P (2009) Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal 3:189–200
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
Bornstein P, Sage EH (1994) Thrombospondins. Methods Enzymol 245:62–85
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
Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927
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
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
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
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
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
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
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
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
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
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
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
Sheehan JM, Shaffrey CI, Jane JA Sr (2001) Degenerative lumbar stenosis: the neurosurgical perspective. Clin Orthop Relat Res 384:61–74
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
Spivak JM (1998) Degenerative lumbar spinal stenosis. J Bone Jt Surg Am 80:1053–1066
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
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
Wynne-Davies R, Walsh WK, Gormley J (1981) Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis. J Bone Jt Surg Br 63B:508–515
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
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
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.
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S.-J. Hyun and B. G. Park equally contributed to the work as a co-first author.
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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
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DOI: https://doi.org/10.1007/s00586-013-2866-6