Dhungana Hemanta， Xiao-xing Jiang*， Zhen-zhou Feng，Zi-xian Chen， and Yuan-wu Cao

Department of Orthopedics， Zhongshan Hospital，F(xiàn)udan University， Shanghai 200032， China

?

Etiology for Degenerative Disc Disease

Dhungana Hemanta， Xiao-xing Jiang*， Zhen-zhou Feng，Zi-xian Chen， and Yuan-wu Cao

Department of Orthopedics， Zhongshan Hospital，F(xiàn)udan University， Shanghai 200032， China

degenerative intervertebral disc disease； cervical spine； genetics； back pain

Degenerative disc disease is a multifaceted progressive irreversible condition and an inevitable part of aging， which has been found to be a contributing factor for low back pain and might cause radiculopathy， myelopathy， spinal stenosis， degenerative spondylolisthesis， and herniations. Its etiology is complex and multifactorial. Although genetics influence more dominant， the occupational and mechanical influences still persist as a major risk factor. This review emphasizes up-to-date knowledge regarding etiology of disc degeneration with special consideration on occupational， lifestyle factors， and genetic polymorphisms.

Chin Med Sci J 2016； 31（3）：185-191

D EGENERATIVE intervertebral disc disease is an inevitable part of aging and found to be one of the contributing factors for low back pain.1Degenerative disc disease （DDD） affects the functional capability of intervertebral disc， making it unable to bear physiological loads， thus leading to damage to structural integrity， formation of disc herniation， osteophyte，and vertebral micro-fracture. Different methods have been used in the past to measure disc degeneration. The disc space height， signal intensity， and bulging are widely used to estimate degenerative changes of intervertebral disc based on computed tomography， magnetic resonance imaging （MRI）， pathology， and autopsy results.2-3However，lack of uniform grading system of disc degeneration impedes progress in the understanding its etiology. DDD has been attributed to various factors such as physical loading， vehicular driving， spinal trauma， smoking， obesity，and genetic influences.4-9The pathogenesis of DDD and its association with environmental and genetic factors is poorly understood. In recent years molecular mechanism of DDD has been widely studied in the various populations. This review concentrates the latest advances on the evidenced factors associated with the occurrence of DDD.

OCCUPATIONAL EFFECTS

Disc degeneration is highly linked to heavy physical loading specific to occupation. Occupational risk factors such as sustained abnormal postures， bending， vibration，twisting， sitting， heavy lifting， have been suspected to be associated with degeneration and herniation of intervertebral disc.10-12Elfering et al13reported that lack of exercise and night shift work were significant predictors for disc degeneration and its progression. In a cross-sectional MRI study， Luoma et al1found that low back pain was morecommon among carpenters and machine workers than among office workers， but timing and signs of disc degeneration are unknown in this study. In another similar study Evans et al14revealed that frequency of degenerative change in lumbar intervertebral disc of sedentary women was high， whereas degenerative change was not found in ambulatory women. However men in this study showed no significance difference in prevalence of degenerative change in lumbar intervertebral disc. Lawrence15found that lumbar intervertebral disc degeneration was more general in miners and manual workers than in business and professional workers. Puustjarvi et al16noted strenuous exercise did not exert adverse influence on the intervertebral disc of young dogs.

Kelsey and Hardy17reported that individual who spends most of the time on driving vehicles tends to have more damage on intervertebral disc regardless of sex. This study also explained the prolonged sitting was associated with back pain or sciatica. Other studies also revealed that vehicle drivers are more prone to lumbar intervertebral disc degeneration than ones with other occupations.12，18，19Occupational drivers often have back problem and degenerative changes of intervertebral disc due to whole body vibration that caused by driving vehicle.7，20

Although it is generally agreed occupational suspected risk factors play an important role in the pathogenesis of the degenerative process， a precise understanding of the biochemical and molecular events occurred in the disc that is exposed to prolonged sitting， heavy lifting， postural stresses and unpleasant environment remains elusive.

LIFE STYLE

Epidemiologic studies revealed smoking is a weak risk indicator but not a cause for disc generation.21-23Smoking has been identified to decrease blood flow to vertebral body，24，25impair fibrinolysis，26raise intra-abdominal pressure because of coughing，27and reduce bone mineral content，28-30which might have direct or indirect effects on intervertebral disc degeneration. Kelsey et al31found no absolute difference between smokers and nonsmokers in cervical disc changes， and smoking plays little role in severity of disease. However， An et al32found smokers have higher risk for the cervical DDD than nonsmokers. Although nicotine-induced degenerative changes are irreversible， Nemoto et al23and Elmasry et al33regarded that smoking cessation is beneficial to regeneration of a degenerated disc to some extent.

Moreover， obesity or increased body mass index are closely related with disc degeneration.6，34，35One study in Japanese population demonstrated that degeneration among young adult men is associated with overweight and abdominal obesity.34Another study by Liuke et al6as well supported the above conclusion. However， a study of a small sample reported by Videman et al36did not find obesity was interrelated with disc degeneration based on signal variation on MRI. Prevention and control of obesity are given priority to lessen the severity of intervertebral disc degeneration.6，35，37However， more studies are needed to figure out the mechanism by which obesity and smoking increase the risk of DDD.

GENETIC FACTORS

Clearly， it is agreed that genetics， as a risk factor for DDD， has dominant influences on etiopathogenesis.9，38，39A case-control study performed by Matsui et al40suggested a strong familial predisposition to development of DDD. They observed significant disc degeneration in patients with a positive family history of disc herniation. Videman et al41examined 150 male twins who were scanned on MRI to record changes in the degenerative signs over a 5-year interval and found a prominent hereditary influences on the progression of DDD. In addition， they reported occupational factors had modest effects （from 2% to 15%） on development of DDD compared to genetic effects （from 47% to 66%）. Another two studies on twins also revealed significant heritability influence on intervertebral disc degeneration.38，42Moreover， environmental factors have been revealed to impact on disc signal variation among the twins in the two studies.

Predisposing genes such as vitamin D receptor （VDR），type I collagen （COL1）， type IX collagen （COL9） A2 and COL9A3， aggrecan， have been proved to have strong relationship with DDD in several ethnic population.43-46

VDR

VDR， a member of nuclear steroid hormone receptor， is supposed to play an important role in normal bone mineralization and remodeling. Many disorders such as osteoporosis， osteoarthritis， and DDD are associated with gene polymorphisms of VDR.47Videman et al44described the association of DDD with VDR in monozygotic twins from Finland. A study of 205 Japanese young adults revealed that Tt genotype of VDR gene was more highly associated with DDD than TT genotype.43A large-scale study in Chinese by Cheung et al47further supported the link between t allele of VDR gene and DDD with an odds ratio of 2.61. Videman et al48concluded that individuals with tt genotype are more prone to suffer from annular rupture.The variant t-allele in different genetic population makes DDD phenotype more diverse.49

COL1

COL1 is a main element of extracellular matrix and a necessary component to provide tensile strength to the intervertebral disc.50Polymorphisms of COL1A1 gene have been identified as likely contributors for disc degeneration in the past studies. Sarver et al51found a decreased COL1 expression in mice would reduce the ability of the disc tissue to withstand mechanical forces. COL1A1 Sp1 polymorphism has been verified to be involved in osteoporosis， increased facture risk and degenerative diseases.52-54Pluijm et al55considered that individual with TT genotype of COL1A1 Sp1 polymorphism had a larger risk for disc degeneration than those with GG and GT genotypes. Similarly， Tilkerdis et al56found strong association of DDD with TT genotype polymorphism of COL1A1 in young male soldiers. Videman et al57suggested variants in the COL1A1 gene that may account for DDD， rs2075555 and rs1007086， were associated with disc signal intensity.

COL9

COL9， a tiny structural component of the cartilage and nucleus， acts as a bridge between non-collagenous and collagenous tissues and gives mechanical support to the disc.58As a heterotrimeric protein， COL9 consists of α chains i.e. α1（IX）， α2（IX）， and α3（IX） that is encoded by COL9A1， COL9A2， and COL9A3 genes respectively.59，60Mutations in COL9 are associated with disc degeneration in animals and human individuals.61The tryptophan 2 （Trp2）and Trp3 alleles may contribute to degenerative disease and symptomatic spinal stenosis.62，63

Annunen et al45identified an allele Trp2 of COL9A2 gene to be involved in the pathogenesis of DDD. α2 chain of COL9 was found in 6 patients among 157 cases with sciatica， but in none of 174 healthy controls. However frequency of the Trp2 allele in this study was typically low（1.9%） and this may be contributed to non-operated symptomatic patients who were not included. Jim et al64performed a case-control study in 804 Chinese volunteers，and the result revealed Trp2 allele was seen in 20% of the study population and increased risk of developing annular tears as well as intervertebral disc degeneration. Higashino et al65found that 21.4% patients carried Trp2 allele in Japanese herniated nucleus pulposus patients younger than 40 years. In contrast， Trp2 allele had no association with disc degeneration for patients older than 40 years，which is different from the result in Chinese patients. However， Trp2 alleles were not associated with DDD in the Southern European patients.66Zhu et al67used immunohistochemical analysis to compare COL9 expression in the normal adult disc with mechanical injuried disc， and found COL9 expression in the degenerative adult disc but not in the normal adult disc.

Trp3 polymorphism of COL9A3 gene was considered to be a risk factor for Finnish disc degeneration patients.46In Southern European population， the frequency of Trp3 allele was 8.6% in intervertebral disc degeneration patients，which was significantly higher than that in the healthy controls （4.9%）.66However， for genotyping studies in Japanese and Chinese population， Trp3 allele showed no link with DDD.64，65Solovieva et al68suggested that association of Trp3 allele with disc degeneration might be modified by interleukin 1 beta gene polymorphism. Rathod et al69found COL9A2 gene polymorphism instead of COL9A3 gene polymorphism might have correlation with DDD in a Indian population.

Aggrecan

Aggrecan， a proteoglycan in the nucleus pulposus of intervertebral disc， acts as a water binding component to make up the highly hydrated core of nucleus pulposus and to maintain the disc in its normal functional state.70Aggrecan can maintain structural integrity， elastic deformability and facilitate intervertebral disc and cartilage to bear compressive forces.71，72The amount of water and aggrecan decreases in the nucleus pulposus cells of degenerative disc.50

Variable number of tandem repeat polymorphisms has been identified in human aggrecan 1 core protein gene，with repeat number ranging from 13 to 33 in exon 12.73，74Kawaguchi et al75found association of tandem repeat polymorphisms with disc degeneration in 64 Japanese female women. Kim et al76found that A21 allele was highly overrepresented among the younger population with multi-level disc degeneration. The findings of the two researches support the idea that genetic factor is more important in the pathogenesis of the degenerative process than occupational and environmental factors because young individuals enrolled in the both studies were less liable to occupational and environmental factors. In addition， studies in Turkey77and Iran78population revealed that multi-level disc degeneration and herniation associated with lower number of tandem repeats of aggrecan gene. Association was also observed in the Finnish population.79However， Roughly et al80did not find correlation between aggrecan gene tandem repeat poly- morphisms and DDD.

In various studies of different populations， VDR， COL1A1，COL9A2， and aggrecan genes and their effects on DDD arealready apparent to us. However， various genetic criteria and small size cohort in studies make the molecular etiopathogenesis of DDD more complex. A clear phenotype definition， long-term follow-up studies with large sample size are required for genetic association to be more understandable， meaningful and successful. Also， more reliable measures would help to know DDD more precisely.

In conclusion， the definite pathogenesis of DDD is not clear yet. By now， it has become evident that disc degeneration is the result of interaction of occupational risk factors，environmental risk factors， and genetic factors. The definition of degenerative disc disease is obscure. Its occurrence and severity are found inconsistent in various studies. So， it is necessary to find the uniform interpretation of DDD. Also，better understanding of the clinical symptoms and likely causes of the pain are equally important and should be studied carefully.

REFERENCES

1. Luoma K， Riihimaki H， Luukkonen R， et al. Low back pain in relation to lumbar disc degeneration. Spine （Phila Pa 1976） 2000； 25：487-92.

2. Videman T， Battie MC， Gill K， et al. Magnetic resonance imaging findings and their relationships in the thoracic and lumbar spine. Insights into the etiopathogenesis of spinal degeneration. Spine （Phila Pa 1976） 1995； 20：928-35.

3. Vernon-Roberts B， Pirie CJ. Degenerative changes in the intervertebral discs of the lumbar spine and their sequelae. Rheumatol Rehabil 1977； 16：13-21.

4. Videman T， Sarna S， Battie MC， et al. The long-term effects of physical loading and exercise lifestyles on back-related symptoms， disability， and spinal pathology among men. Spine （Phila Pa 1976） 1995； 20：699-709.

5. Oda H， Matsuzaki H， Tokuhashi Y， et al. Degeneration of intervertebral discs due to smoking： experimental assessment in a rat-smoking model. J Orthop Sci 2004；9：135-41.

6. Liuke M， Solovieva S， Lamminen A， et al. Disc degeneration of the lumbar spine in relation to overweight. Int J Obes （Lond） 2005； 29：903-8.

7. Kumar A， Varghese M， Mohan D， et al. Effect of whole-body vibration on the low back. A study of tractor-driving farmers in north India. Spine （Phila Pa 1976） 1999； 24：2506-15.

8. Videman T， Battie MC， Gibbons LE， et al. Lifetime exercise and disk degeneration： an MRI study of monozygotic twins. Med Sci Sports Exerc 1997； 29：1350-6.

9. Postacchini F， Lami R， Pugliese O. Familial predisposition to discogenic low-back pain. An epidemiologic and immunogenetic study. Spine （Phila Pa 1976） 1988；13：1403-6.

10. Williams FM， Sambrook PN. Neck and back pain and intervertebral disc degeneration： role of occupational factors. Best Pract Res Clin Rheumatol 2011； 25：69-79.

11. Videman T， Levalahti E， Battie MC. The effects of anthropometrics， lifting strength， and physical activities in disc degeneration. Spine （Phila Pa 1976） 2007；32：1406-13.

12. Seidler A， Bergmann A， Jager M， 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.

13. Elfering A， Semmer N， Birkhofer D， et al. Risk factors for lumbar disc degeneration： a 5-year prospective MRI study in asymptomatic individuals. Spine （Phila Pa 1976）2002； 27：125-34.

14. Evans W， Jobe W， Seibert C. A cross-sectional prevalence study of lumbar disc degeneration in a working population. Spine （Phila Pa 1976） 1989； 14：60-4.

15. Lawrence JS. Disc degeneration. Its frequency and relationship to symptoms. Ann Rheum Dis 1969； 28：121-38.

16. Puustjarvi K， Lammi M， Helminen H， et al. Proteoglycans in the intervertebral disc of young dogs following strenuous running exercise. Connect Tissue Res 1994；30：225-40.

17. Kelsey JL， Hardy RJ. Driving of motor vehicles as a risk factor for acute herniated lumbar intervertebral disc. Am J Epidemiol 1975； 102：63-73.

18. Bovenzi M， Hulshof CT. An updated review of epidemiologic studies on the relationship between exposure to whole-body vibration and low back pain （1986-1997）. Int Arch Occup Environ Health 1999； 72：351-65.

19. Hoogendoorn WE， van Poppel MN， et al. Physical load during work and leisure time as risk factors for back pain. Scand J Work Environ Health 1999； 25：387-403.

20. Lings S， Leboeuf-Yde C. Whole-body vibration and low back pain： a systematic， critical review of the epidemiological literature 1992-1999. Int Arch Occup Environ Health 2000； 73：290-7.

21. Leboeuf-Yde C. Smoking and low back pain. A systematic literature review of 41 journal articles reporting 47 epidemiologic studies. Spine （Phila Pa 1976） 1999；24：1463-70.

22. Wang D， Nasto LA， Roughley P， et al. Spine degeneration in a murine model of chronic human tobacco smokers. Osteoarthritis Cartilage 2012； 20：896-905.

23. Nemoto Y， Matsuzaki H， Tokuhasi Y， et al. Histologicalchanges in intervertebral discs after smoking and cessation： experimental study using a rat passive smoking model. J Orthop Sci 2006； 11：191-7.

24. Battie MC， Videman T， Gill K， et al. 1991 Volvo Award in clinical sciences. Smoking and lumbar intervertebral disc degeneration： an MRI study of identical twins. Spine（Phila Pa 1976） 1991； 16：1015-21.

25. Ernst E. Smoking， a cause of back trouble？ Br J Rheumatol 1993； 32：239-42.

26. Jayson MI， Keegan A， Million R， et al. A fibrinolytic defect in chronic back pain syndromes. Lancet 1984； 2：1186-7.

27. Kelsey JL. An epidemiological study of acute herniated lumbar intervertebral discs. Rheumatol Rehabil 1975；14：144-59.

28. Valimaki MJ， Karkkainen M， Lamberg-Allardt C， et al. Exercise， smoking， and calcium intake during adolescence and early adulthood as determinants of peak bone mass. Cardiovascular Risk in Young Finns Study Group. BMJ 1994； 309：230-5.

29. Ortego-Centeno N， Munoz-Torres M， Hernandez-Quero J，et al. Bone mineral density， sex steroids， and mineral metabolism in premenopausal smokers. Calcif Tissue Int 1994； 55：403-7.

30. Daniell HW. Osteoporosis of the slender smoker. Vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Arch Intern Med 1976； 136：298-304.

31. Kelsey JL， Githens PB， Walter SD， et al. An epidemiological study of acute prolapsed cervical intervertebral disc. J Bone Joint Surg Am 1984； 66：907-14.

32. An HS， Silveri CP， Simpson JM， et al. Comparison of smoking habits between patients with surgically confirmed herniated lumbar and cervical disc disease and controls. J Spinal Disord 1994； 7：369-73.

33. Elmasry S， Asfour S， de Rivero， et al. Effects of tobacco smoking on the degeneration of the intervertebral disc： a finite element study. PLoS One 2015； 10：e0136137.

34. Takatalo J， Karppinen J， Taimela S， et al. Association of abdominal obesity with lumbar disc degeneration|a magnetic resonance imaging study. PLoS One 2013；8：e56244.

35. Samartzis D， Karppinen J， Chan D， et al. The association of lumbar intervertebral disc degeneration on magnetic resonance imaging with body mass index in overweight and obese adults： a population-based study. Arthritis Rheum 2012； 64：1488-96.

36. Videman T， Gibbons LE， Kaprio J， et al. Challenging the cumulative injury model： positive effects of greater body mass on disc degeneration. Spine J 2010； 10：26-31.

37. Hangai M， Kaneoka K， Kuno S， et al. Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J 2008； 8：732-40.

38. Sambrook PN， MacGregor AJ， Spector TD. Genetic influences on cervical and lumbar disc degeneration： a magnetic resonance imaging study in twins. Arthritis Rheum 1999； 42：366-72.

39. Battie MC， Haynor DR， Fisher LD， et al. Similarities in degenerative findings on magnetic resonance images of the lumbar spines of identical twins. J Bone Joint Surg Am 1995； 77：1662-70.

40. Matsui H， Kanamori M， Ishihara H， et al. Familial predisposition for lumbar degenerative disc disease. A case-control study. Spine （Phila Pa 1976） 1998；23：1029-34.

41. Videman T， Battie MC， Ripatti S， et al. Determinants of the progression in lumbar degeneration： a 5-year followup study of adult male monozygotic twins. Spine （Phila Pa 1976） 2006； 31：671-8.

42. Battie MC， Videman T， Gibbons LE， et al. 1995 Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging findings in identical twins. Spine （Phila Pa 1976） 1995； 20：2601-12.

43. Kawaguchi Y， Kanamori M， Ishihara H， et al. The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 2002；84-A：2022-8.

44. Videman T， Leppavuori J， Kaprio J， et al. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine （Phila Pa 1976） 1998； 23：2477-85.

45. Annunen S， Paassilta P， Lohiniva J， et al. An allele of COL9A2 associated with intervertebral disc disease. Science 1999； 285：409-12.

46. Paassilta P， Lohiniva J， Goring HH， et al. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 2001； 285：1843-9.

47. Cheung KM， Chan D， Karppinen J， et al. Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine（Phila Pa 1976） 2006； 31：1143-8.

48. Videman T， Gibbons LE， Battie MC， et al. The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density. Spine （Phila Pa 1976） 2001； 26：E7-E12.

49. Uitterlinden AG， Fang Y， Van Meurs JB， et al. Genetics and biology of vitamin D receptor polymorphisms. Gene 2004；338：143-56.

50. Antoniou J， Steffen T， Nelson F， et al. The human lumbar intervertebral disc： evidence for changes in the biosyn-thesis and denaturation of the extracellular matrix with growth， maturation， ageing， and degeneration. J Clin Invest 1996； 98：996-1003.

51. Sarver JJ， Elliott DM. Altered disc mechanics in mice genetically engineered for reduced type I collagen. Spine（Phila Pa 1976） 2004； 29：1094-8.

52. Williams FM， Spector TD. The genetics of osteoporosis. Acta Reumatol Port 2007； 32：231-40.

53. Keen RW， Woodford-Richens KL， Grant SF， et al. Association of polymorphism at the type I collagen（COL1A1） locus with reduced bone mineral density，increased fracture risk， and increased collagen turnover. Arthritis Rheum 1999； 42：285-90.

54. Grant SF， Reid DM， Blake G， et al. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 1996； 14：203-5.

55. Pluijm SM， van Essen HW， Bravenboer N， et al. Collagen type I alpha1 Sp1 polymorphism， osteoporosis， and intervertebral disc degeneration in older men and women. Ann Rheum Dis 2004； 63：71-7.

56. Tilkeridis C， Bei T， Garantziotis S， et al. Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits. J Med Genet 2005； 42：e44.

57. Videman T， Saarela J， Kaprio J， et al. Associations of 25 structural， degradative， and inflammatory candidate genes with lumbar disc desiccation， bulging， and height narrowing. Arthritis Rheum 2009； 60：470-81.

58. Eyre DR， Matsui Y， Wu JJ. Collagen polymorphisms of the intervertebral disc. Biochem Soc Trans 2002； 30：844-8.

59. Paassilta P， Pihlajamaa T， Annunen S， et al. Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem 1999； 274：22469-75.

60. Pihlajamaa T， Vuoristo MM， Annunen S， et al. Human COL9A1 and COL9A2 genes. Two genes of 90 and 15 kb code for similar polypeptides of the same collagen molecule. Matrix Biol 1998； 17：237-41.

61. Boyd LM， Richardson WJ， Allen KD， et al. Early-onset degeneration of the intervertebral disc and vertebral end plate in mice deficient in type IX collagen. Arthritis Rheum 2008； 58：164-71.

62. Noponen-Hietala N， Kyllonen E， Mannikko M， et al. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003； 62：1208-14.

63. Matsui Y， Mirza SK， Wu JJ， et al. The association of lumbar spondylolisthesis with collagen IX tryptophan alleles. J Bone Joint Surg Br 2004； 86：1021-6.

64. Jim JJ， Noponen-Hietala N， Cheung KM， et al. The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine （Phila Pa 1976） 2005； 30：2735-42.

65. Higashino K， Matsui Y， Yagi S， et al. 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； 31：107-11.

66. Kales SN， Linos A， Chatzis C， et al. The role of collagen IX tryptophan polymorphisms in symptomatic intervertebral disc disease in Southern European patients. Spine （Phila Pa 1976） 2004； 29：1266-70.

67. Zhu Y， Wu JJ， Weis MA， et al. Type IX collagen neodeposition in degenerative discs of surgical patients whether genotyped plus or minus for COL9 risk alleles. Spine （Phila Pa 1976） 2011； 36：2031-8.

68. Solovieva S， Lohiniva J， Leino-Arjas P， et al. Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 2006； 15：613-9.

69. Rathod TN， Chandanwale AS， Gujrathi S， et al. Association between single nucleotide polymorphism in collagen IX and intervertebral disc disease in the Indian population. Indian J Orthop 2012； 46：420-6.

70. Sztrolovics R， Alini M， Roughley PJ， et al. Aggrecan degradation in human intervertebral disc and articular cartilage. Biochem J 1997； 326：235-41.

71. Cs-Szabo G， Ragasa-San Juan D， Turumella V， et al. Changes in mRNA and protein levels of proteoglycans of the anulus fibrosus and nucleus pulposus during intervertebral disc degeneration. Spine （Phila Pa 1976） 2002；27：2212-9.

72. Urban JP， McMullin JF. Swelling pressure of the lumbar intervertebral discs： influence of age， spinal level， composition， and degeneration. Spine （Phila Pa 1976） 1988；13：179-87.

73. Doege KJ， Coulter SN， Meek LM， et al. A human-specific polymorphism in the coding region of the aggrecan gene. Variable number of tandem repeats produce a range of core protein sizes in the general population. J Biol Chem 1997； 272：13974-9.

74. Roughley PJ， Alini M， Antoniou J. The role of proteoglycans in aging， degeneration and repair of the intervertebral disc. Biochem Soc Trans 2002； 30：869-74.

75. Kawaguchi Y， Osada R， Kanamori M， et al. Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine （Phila Pa 1976） 1999； 24：2456-60.

76. Kim NK， Shin DA， Han IB， et al. The association of aggrecan gene polymorphism with the risk of intervertebral disc degeneration. Acta Neurochir （Wien） 2011； 153：129-33.

77. Eser B， Cora T， Eser O， et al. Association of the polymor-phisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomarkers 2010； 14：313-7.

78. Mashayekhi F， Shafiee G， Kazemi M， et al. Lumbar disk degeneration disease and aggrecan gene polymorphism in northern Iran. Biochem Genet 2010； 48：684-9.

79. Solovieva S， Noponen N， Mannikko M， et al. Association between the aggrecan gene variable number of tandem repeats polymorphism and intervertebral disc degeneration. Spine （Phila Pa 1976） 2007； 32：1700-5.

80. Roughley P， Martens D， Rantakokko J， et al. The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage. Eur Cell Mater 2006； 11：1-7； discussion 7.

for publication November 17， 2015.

Tel： 86-13901790767， E-mail： jiang.xiaoxing@ zs-hospital.sh.cn