European Spine Journal

, Volume 17, Issue 5, pp 626–643

Pharmacological enhancement of disc diffusion and differentiation of healthy, ageing and degenerated discs

Results from in-vivo serial post-contrast MRI studies in 365 human lumbar discs
  • S. Rajasekaran
  • K. Venkatadass
  • J.  Naresh Babu
  • K. Ganesh
  • Ajoy P. Shetty
Original Article

Abstract

Degenerative disc disease (DDD) is still a poorly understood phenomenon because of the lack of availability of precise definition of healthy, ageing and degenerated discs. Decreased nutrition is the final common pathway for DDD and the status of the endplate (EP) plays a crucial role in controlling the extent of diffusion, which is the only source of nutrition. The vascular channels in the subchondral plate have muscarinic receptors but the possibility of enhancing diffusion pharmacologically by dilation of these vessels has not been probed. Although it is well accepted that EP damage will affect diffusion and thereby nutrition, there is no described method to quantify the extent of EP damage. Precise definitions with an objective method of differentiating healthy, ageing and degenerated discs on the basis of anatomical integrity of the disc and physiological basis of altered nutrition will be useful. This information is an urgent necessity for better understanding of DDD and also strategizing prevention and treatment.

Seven hundred and thirty endplates of 365 lumbar discs from 73 individuals (26 healthy volunteers and 47 patients) with age ranging from 10–64 years were evaluated by pre-contrast and 10 min, 2, 4, 6 and 12 h post contrast MRI after IV injection of 0.3 mmol/kg of Gadodiamide. End plates were classified according to the extent of damage into six grades and an incremental score was given for each category. A total endplate score (TEPS) was derived by adding the EP score of the two endplates for each concerned disc. The base line value (SIbase) and the signal intensity at particular time periods were used to derive the enhancement percentage for each time period (Enhancement (%) = SItp – SIbase/SIbase × 100). The enhancement percentage for each time period, the time for peak enhancement (T-max) and the time intensity curve (TIC) over 12 h were used to study and compare the diffusion characteristics. The differences in pattern of diffusion were obvious visually at 4 h which was categorized into five patterns—Pattern A representing normal diffusion to Pattern E representing a total abnormality in diffusion. Degeneration was classified according to Pfirrmann’s grading and this was correlated to the TEPS and the alterations in diffusion patterns. The relationship of TEPS on the increase in DDD was evaluated by a logistic curve and the cut point for severe DDD was found by ROC curve. The influence of the variables of age, level, Modic changes, instability, annulus fibrosis defect (DEBIT), TEPS and diffusion patterns on DDD was analyzed by multiple and stepwise regression analysis.

Oral nimodipine study: Additional forty lumbar end-plates from four young healthy volunteers were studied to document the effect of oral nimodipine. Pre-drug diffusion levels were studied by pre and post contrast MRI (0.3 mmol/kg of gadodiamide) at 10 min, 2, 4, 6, 12 and 24 h. Oral nimodipine was administered (30 mg QID) for 5 days and post-contrast MRI studies were performed similarly. Enhancement was calculated at vertebral body-VB; subchondral bone-SCB; Endplate Zone-EPZ and at superior and inferior peripheral nucleus pulposus-PNP and central nucleus pulposus-CNP, using appropriate cursors by a blinded investigator. Paired sample t test and area under curve (AUC) measurements were done.

The incidence of disc degeneration had a significant correlation with increasing TEPS (Trend Chi-square, P < 0.01). Only one out of 83 (1.2%) disc had either Pfirrmann Grade IV or V when the score was 4 or below when compared to 34/190 (17.9%) for scores 5–7; 41 of 72 (56.9%) for scores 8–10 and 18 of 20 (90%) for scores 11 and 12 (P < 0.001 for all groups). Pearson’s correlation between TEPS and DDD was statistically significant, irrespective of the level of disc or different age groups (r value was above 0.6 and P < 0.01 for all age groups). Logistic curve fit analysis and ROC curve analysis showed that the incidence of DDD increased abruptly when the TEPS crossed six. With a progressive increase of end plate damage, five different patterns of diffusion were visualized. Pattern D and E represented totally altered diffusion pattern questioning the application of biological method of treatment in such situations. Four types of time intensity curves (TIC) were noted which helped to differentiate between healthy, aged and degenerated discs. Multiple and stepwise regression analysis indicated that pattern of disc diffusion and TEPS to be the most significant factors influencing DDD, irrespective of age.

Nimodipine increased the average signal intensity for all regions—by 7.6% for VB, 8% for SCB and EPZ and 11% for CNP at all time intervals (P < 0.01 for all cases). Although the increase was high at all time intervals, the maximum increase was at 2 h for VB, SCB and EPZ; 4 h for PNP and 12 h for CNP. It was also interesting that post-nimodipine, the peak signal intensity was attained early, was higher and maintained longer compared to pre-nimodipine values.

Our study has helped to establish that EP damage as a crucial event leading to structural failure thereby precipitating DDD. An EP damage score has been devised which had a good correlation to DDD and discs with a score of six and above can be considered ‘at risk’ for severe DDD. New data on disc diffusion patterns were obtained which may help to differentiate healthy, ageing and degenerated discs in in-vivo conditions. This is also the first study to document an increase in diffusion of human lumbar discs by oral nimodipine and poses interesting possibility of pharmacological enhancement of lumbar disc nutrition.

Keywords

Disc degeneration End plate Post-contrast diffusion Ageing Nimodipine 

Abbreviations

MRI

Magnetic resonance imaging

EP

End plate

EPZ

End plate zone

NP

Nucleus pulposus

SCB

Sub-chondral bone

VB

Vertebral body

PNP

Peripheral nucleus pulposus

CNP

Central nucleus pulposus

DDD

Degenerative disc disease

AFD

Annulus fibrosus defect

TEPS

Total end plate score

EPD

End plate defect

Tmax

Time taken to achieve peak enhancement percentage

SI

Signal intensity

SIbase

Baseline signal intensity in pre-contrast MRI

SImax

Maximum signal intensity within 12 h

SItp

Signal intensity at a particular time period

References

  1. 1.
    Adams MA, Freeman BJC, Morrison HP, Nelson IW, Dolan P (2000) Mechanical initiation of intervertebral disc degeneration. Spine 25:1625–1636PubMedCrossRefGoogle Scholar
  2. 2.
    Adams MA, Roughley PJ (2006) What is intervertebral disc degeneration, and what causes it? Spine 31:2151–2161PubMedCrossRefGoogle Scholar
  3. 3.
    An HS, Takegami K, Kamada H et al (2005) Intradiscal administration of osteogenic protein-1 increases intervertebral disc height and proteoglycan content in the nucleus pulposus in normal adolescent rabbits. Spine 30:25–31 (discussion-2)PubMedGoogle Scholar
  4. 4.
    Annunen S, Paassilta P, Lohiniva J et al (1999) An allele of COL9A2 associated with intervertebral disc disease. Science 285:409–412PubMedCrossRefGoogle Scholar
  5. 5.
    Antoniou J, Goudsouzian NM, Heathfield TF et al (1996) The human lumbar endplate: Evidence of changes in biosynthesis and denaturation of the extra-cellular matrix with growth, maturation, ageing, and degeneration. Spine 21:1153–1161PubMedCrossRefGoogle Scholar
  6. 6.
    Ariga K, Miyamoto S, Nakase T et al (2001) The relationship between apoptosis of endplate chondrocytes and ageing and degeneration of the intervertebral disc. Spine 26:2414–2420PubMedCrossRefGoogle Scholar
  7. 7.
    Benoist M (2003) Natural history of the ageing spine. Eur Spine J 12(Suppl 2):S86–S89PubMedCrossRefGoogle Scholar
  8. 8.
    Bernick S, Caillet R (1982) Vertebral end-plate changes with ageing of human vertebrae. Spine 7:97–102PubMedCrossRefGoogle Scholar
  9. 9.
    Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG (2002) Classification of age-related changes in lumbar intervertebral discs. Spine 27:2631–2644PubMedCrossRefGoogle Scholar
  10. 10.
    Brown MF, Hukkanen MVJ, McCarthy ID, Redfern DRM,Batten JJ,Crock HV,Hughes SPF, Polak JM (1997) Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease. J Bone Joint Surg Br 79-B:147–153CrossRefGoogle Scholar
  11. 11.
    Buckwalter JA (1982) Fine structural studies of the human intervertebral disc.In: White AA, Gorden SL (eds) Idiopathic low back pain. CV Mosby, St. Louis, pp 108–43Google Scholar
  12. 12.
    Buckwalter JA (1995) Spine update: ageing and degeneration of the human intervertebral disc. Spine 20:1307–1314PubMedGoogle Scholar
  13. 13.
    Cerny LC, Stasiw DM, Zuk W (1981) The logistic curve for the fitting of sigmoidal data. Physiol Chem Phys 13(3):221–230PubMedGoogle Scholar
  14. 14.
    Cheung KM, Ho G, Leung VY et al (2005) The effect of severity of disc degeneration on mesenchymal stem cells’ ability to regenerate the intervertebral disc: a rabbit model. Eur Cell Mater 10(Suppl 3):45Google Scholar
  15. 15.
    Crean JK, Roberts S, Jaffray DC et al. Matrix metalloproteinases in the human intervertebral disc: role in disc degeneration and scoliosis. Spine 199, 722:2877–2884Google Scholar
  16. 16.
    Edwards WT, Zheng Y, Ferrara LA, Yuan HA (2001) Structural features and thickness of the vertebral cortex in the thoracolumbar spine. Spine 26:218–225PubMedCrossRefGoogle Scholar
  17. 17.
    Eyre DR (1988) Collagens of the disc. In: Ghosh P (eds) The biology of the intervertebral disc, vol I. CRC Press, Inc., Boca Raton, pp 171–188Google Scholar
  18. 18.
    Goel VK, Monroe BT, Gilbertson LG et al (1995) Interlaminar shear stresses and laminae separation in a disc. Spine 20:689–698PubMedGoogle Scholar
  19. 19.
    Goupille P, Jayson MI, Valat JP, Freemont AJ (1998) Matrix metalloproteinases: the clue to intervertebral disc degeneration? Spine 23:612–626CrossRefGoogle Scholar
  20. 20.
    Greenfield ML, Kuhn JE, Wojtys EM (1998) A statistics primer: validity and reliability. Am J Sports Med 26:483–485PubMedGoogle Scholar
  21. 21.
    Gruber HE, Hanley EN Jr (2003) Recent advances in disc cell biology. Spine 28:186–193PubMedCrossRefGoogle Scholar
  22. 22.
    Hernández-Hernández R, Coll T, Rachitzky P, Armas-Hernández MJ, Armas-Padilla MC, Velasco M, Rizzo A (2002) Comparison of two nimodipine formulations in healthy volunteers. J Hum Hypertens 16(S1):S142–S144PubMedCrossRefGoogle Scholar
  23. 23.
    Holm S, Holm AK, Ekstrom L et al (2004) Experimental disc degeneration due to endplate injury. J Spinal Disord Tech 17:64–71PubMedCrossRefGoogle Scholar
  24. 24.
    Holm S, Nachemson A (1988) Nutrition of the intervertebral disc: acute effects of cigarette smoking. An experimental animal study. Ups J Med Sci 93:91–99PubMedGoogle Scholar
  25. 25.
    Hutton WC, Elmer WA, Boden SD et al (1999) The effect of hydrostatic pressure on intervertebral disc metabolism. Spine 24:1507–1515PubMedCrossRefGoogle Scholar
  26. 26.
    Hutton WC, Toribatake Y, Elmer WA et al (1998) The effect of compressive force applied to the intervertebral disc in vivo: a study of proteoglycans and collagen. Spine 23:2524–2537PubMedCrossRefGoogle Scholar
  27. 27.
    Hutton WC, Yoon ST, Elmer WA et al (2002) Effect of tail suspension (or simulated weightlessness) on the lumbar intervertebral disc: study of proteoglycans and collagen. Spine 27:1286–1290PubMedCrossRefGoogle Scholar
  28. 28.
    Ibrahim MA, Haughton VM, Hyde JS (1995) Effect of disk maturation on diffusion of low molecular weight gadolinium complexes:An experimental study in rabbits. Am J Neuroradiol 16:1307–1311PubMedGoogle Scholar
  29. 29.
    Ibrahim MA.,Jesmanowicz A, Hyde JS et al (1994) Contrast enhancement of normal intervertebral disks: time and dose dependance. Am J Neuroradiol 15:419–423PubMedGoogle Scholar
  30. 30.
    Ishihara H, McNally DS, Urban JPG et al (1996) Effects of hydrostatic pressure on matrix synthesis in different regions of the intervertebral disk. J Appl Physiol 80:839–846PubMedGoogle Scholar
  31. 31.
    Ishihara H, Urban JP (1999) Effects of low oxygen concentrations and metabolic inhibitors on proteoglycan and protein synthesis rates in the intervertebral disc. J Orthop Res 17:829–835PubMedCrossRefGoogle Scholar
  32. 32.
    Jensen MC, Kelly AP, Brant-Zawadzki MN (1994) MRI of degenerative disease of the lumbar spine. Magn Reson Q 10:173–190PubMedGoogle Scholar
  33. 33.
    Kang JD, Stefanovic-Racic M, McIntyre LA et al (1997) Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2 and matrix metalloproteinases. Spine 22:1065–1073PubMedCrossRefGoogle Scholar
  34. 34.
    Kauppila LI (1997) Prevalence of stenotic changes in arteries supplying the lumbar spine. A postmortem angiographic study on 140 subjects. Ann Rheum Dis 56:591–595PubMedCrossRefGoogle Scholar
  35. 35.
    Kawakami M, Matsumoto T, Hashizume H et al (2005) Osteogenic protein-1 (osteogenic protein-1/bone morphogenetic protein-7) inhibits degeneration and pain-related behavior induced by chronically compressed nucleus pulposus in the rat. Spine 30:1933–1939PubMedCrossRefGoogle Scholar
  36. 36.
    Kawaguchi Y, Osada R, Kanamori M et al (1999) Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine 24:2456–2460PubMedCrossRefGoogle Scholar
  37. 37.
    Kim Y (2000) Prediction of peripheral tears in the annulus of the intervertebral disc. Spine 25:1771–1774PubMedCrossRefGoogle Scholar
  38. 38.
    Kurunlahti M, Tervonen O, Vanharanta H et al (1999) Association of atherosclerosis with low back pain and the degree of disc degeneration. Spine 24:2080–2084PubMedCrossRefGoogle Scholar
  39. 39.
    Li X, Leo BM, Beck G et al (2004) Collagen and proteoglycan abnormalities in the GDF-5-deficient mice and molecular changes when treating disk cells with recombinant growth factor. Spine 29:2229–2234PubMedCrossRefGoogle Scholar
  40. 40.
    Lotz JC, Chin JR (2000) Intervertebral disc cell death is dependent on the magnitude and duration of spinal loading. Spine 25:1477–1482PubMedCrossRefGoogle Scholar
  41. 41.
    Lotz JC, Hsieh AH, Walsh AL et al (2002) Mechanobiology of the intervertebral disc. Biochem Soc Trans 30:853–858PubMedCrossRefGoogle Scholar
  42. 42.
    Lu YM, Hutton WC, Gharpuray VM (1996) Do bending, twisting, and diurnal fluid changes in the disc affect the propensity to prolapse? A viscoelastic finite element model. Spine 21:2570–2579PubMedCrossRefGoogle Scholar
  43. 43.
    MacLean JJ, Lee CR, Grad S et al (2003) Effects of immobilization and dynamic compression on intervertebral disc cell gene expression in vivo. Spine 28:973–981PubMedCrossRefGoogle Scholar
  44. 44.
    Martin MD, Boxell CM, Malone DG (2002) Pathophysiology of lumbar disc degeneration: a review of the literature. Neurosurg Focus 13:1–6CrossRefGoogle Scholar
  45. 45.
    Modic MT, Steinberg PM, Ross JS et al (1988) Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 166:193–199PubMedGoogle Scholar
  46. 46.
    Moore RJ (2006) The vertebral endplate: disc degeneration, disc regeneration. Eur Spine J 15(Suppl. 3):S333–S337 (Review)PubMedCrossRefGoogle Scholar
  47. 47.
    Moore RJ, Vernon-Roberts B, Fraser RD et al (1996) The origin and fate of herniated lumbar intervertebral disc tissue. Spine 21:2149–2155PubMedCrossRefGoogle Scholar
  48. 48.
    Nachemson AL (1992) Newest knowledge of low back pain: a critical look. Clin Orthop 279:8–20PubMedGoogle Scholar
  49. 49.
    Natarajan RN, Andersson GBJ (1999) The influence of lumbar disc height and cross-sectional area on the mechanical response of the disc to physiologic loading. Spine 24:1873–1881PubMedCrossRefGoogle Scholar
  50. 50.
    Natarajan RN, Ke JH, Andersson GBJ (1994) A model to study the disc degeneration process. Spine 19:259–265PubMedCrossRefGoogle Scholar
  51. 51.
    Nguyen CM, Haughton VM, Papke RA, An H, Censky SC (1998) Measuring diffusion of solutes into intervertebral disks with MR imaging and paramagnetic contrast medium. Am J Neuroradiol 19:1781–1784Google Scholar
  52. 52.
    Nguyen CM, Riley L, Ho KC, Xu R, An H, Haughton VM (1997) Effect of degeneration of the intervertebral discs on the process of diffusion. Am J Neuroradiol 18:435–442Google Scholar
  53. 53.
    Nishida K, Kang JD, Gilbertson LG et al (1999) Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine 24:2419–2425PubMedCrossRefGoogle Scholar
  54. 54.
    Oda J, Tanaka H, Tsuzuki N (1988) Intervertebral disc changes with ageing of human cervical vertebra from the neonate to the eighties. Spine 13:1205–1211PubMedCrossRefGoogle Scholar
  55. 55.
    Palmgren T, Gronblad M, Virri J et al (1999) An immunohistochemical study of nerve structures in the annulus fibrosus of human normal lumbar intervertebral discs. Spine 24:2075–2079PubMedCrossRefGoogle Scholar
  56. 56.
    Paul R, Haydon RC, Cheng H et al (2003) Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine 28:755–763PubMedCrossRefGoogle Scholar
  57. 57.
    Pfirrmann CWA, Metzdorf A, Zanetti M et al (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 26:1873–1878PubMedCrossRefGoogle Scholar
  58. 58.
    Qian M, Gallo JM (1992) High-performance liquid chromatographic determination of the calcium channel blocker nimodipine in monkey plasma. J Chromatogr 578(2):316–320PubMedCrossRefGoogle Scholar
  59. 59.
    Rajasekaran S, Naresh Babu J, Arun R et al (2004) ISSLS prize winner. A study of diffusion in human lumbar discs. Spine 29:2654–2667PubMedCrossRefGoogle Scholar
  60. 60.
    Rajasekaran S, Naresh-Babu J, Murugan S (2007) Review of postcontrast MRI studies on diffusion of human lumbar discs. J Magn Reson Imaging 25(2):410–8 (Review)PubMedCrossRefGoogle Scholar
  61. 61.
    Roberts S, Caterson B, Menage J et al (2000) Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine 25:3005–3013PubMedCrossRefGoogle Scholar
  62. 62.
    Roberts S, Menage J, Urban JP (1989) Biochemical and structural properties of the cartilage end-plate and its relation to the intervertebral disc. Spine 14:166–174PubMedCrossRefGoogle Scholar
  63. 63.
    Roberts S, Urban JPG, Evans H et al (1996) Transport properties of the human cartilage endplate in relation to its composition and calcification. Spine 21:415–420PubMedCrossRefGoogle Scholar
  64. 64.
    Roberts S, Caterson B, Evans H et al (1994) Proteoglycan components of the intervertebral disc and cartilage endplate: an immunolocalisation study of animal and human tissues. Histochem J 26:402–411PubMedCrossRefGoogle Scholar
  65. 65.
    Roughley PJ, Alini M, Antoniou J (2002) The role of proteoglycans in ageing, degeneration and repair of the intervertebral disc. Biochem Soc Trans 30:869–874PubMedCrossRefGoogle Scholar
  66. 66.
    Sakai D, Mochida J, Yamamoto Y et al (2003) Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials 24:3531–3541PubMedCrossRefGoogle Scholar
  67. 67.
    Sakai D, Mochida J, Iwashina T et al (2005) Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine 30:2379–2387PubMedCrossRefGoogle Scholar
  68. 68.
    Satoh K, Konno S, Nishiyama et al (1999) Presence and distribution of antigen-antibody complexes in the herniated nucleus pulposus. Spine 24:1980–1984PubMedCrossRefGoogle Scholar
  69. 69.
    Sauerland K, Raiss RX, Steinmeyer J (2003) Proteoglycan metabolism and viability of articular cartilage explants as modulated by the frequency of intermittent loading. Osteoarthritis Cartil 11:343–350CrossRefGoogle Scholar
  70. 70.
    Stairman JW, Holm S, Urban JPG (1991) Factors influencing oxygen concentration gradients in the intervertebral disk: a theoretical analysis. Spine 16:444–449CrossRefGoogle Scholar
  71. 71.
    Tanaka M, Nakahara S, Inoue H (1993) A pathologic study of discs in the elderly. Separation between the cartilaginous endplate and the vertebral body. Spine 18:1456–1462PubMedCrossRefGoogle Scholar
  72. 72.
    Takahashi M, Haro H, Wakabayashi Y et al (2001) 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 83:491–495PubMedCrossRefGoogle Scholar
  73. 73.
    Takegami K, An HS, Kumano F et al (2005) Osteogenic protein-1 is most effective in stimulating nucleus pulposus and annulus fibrosus cells to repair their matrix after chondroitinase ABC-induced in vitro chemonucleolysis. Spine J 5:231–238PubMedCrossRefGoogle Scholar
  74. 74.
    Turgut M, Uysal A, Uslu S, Tavus N, Yurtseven ME (2003) The effects of calcium channel antagonist nimodipine on end-plate vascularity of the degenerated intervertebral disc in rats. J Clin Neurosci 10(2):219–223PubMedCrossRefGoogle Scholar
  75. 75.
    Urban JP, Holm S, Maroudas A (1978) Diffusion of small solutes into the intervertebral disc: as in vivo study. Biorheology 15:203–221PubMedGoogle Scholar
  76. 76.
    Urban JPG, Maroudas A (1979) Measurement of fixed charge density and partition coefficients in the intervertebral disc. Biochim Biophys Acta 586:166–178Google Scholar
  77. 77.
    Vernon-Roberts B (1992) Age-related and degenerative pathology of intervertebral discs and apophyseal joints. In: Jayson MIV (ed) The lumbar spine and back pain, 4th edn. Churchill Livingstone, Edinburgh, pp 17–41Google Scholar
  78. 78.
    Videman T, Sarna S, Battie MC et al (1995) The long-term effect of physical loading and exercise lifestyles on back-related symptoms, disability and spine pathology among men. Spine 20:699–709PubMedCrossRefGoogle Scholar
  79. 79.
    Wallach CJ, Sobajima S, Watanabe Y et al (2003) Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine 28:2331–2337PubMedCrossRefGoogle Scholar
  80. 80.
    Wallace AL, Wyatt BC, McCarthy ID, Hughes SP (1994) Humoral regulation of blood flow in the vertebral endplate. Spine 19(12):1324–1328PubMedGoogle Scholar
  81. 81.
    Walsh AJ, Lotz JC (2004) Biological response of the intervertebral disc to dynamic loading. J Biomech 37:329–337PubMedCrossRefGoogle Scholar
  82. 82.
    Weiler C, Nerlich AG, Zipperer J et al (2002) SSE award competition in basic sciences: expression of major matrix metalloproteinases is associated with intervertebral disc degeneration and resorption. Eur Spine J 11:308–320PubMedCrossRefGoogle Scholar
  83. 83.
    Yoon ST, Park JS, Kim KS et al (2004) ISSLS prize winner: LMP-1 upregulates intervertebral disc cell production of proteoglycans and BMPs in vitro and in vivo. Spine 29:2603–2611PubMedCrossRefGoogle Scholar
  84. 84.
    Zhang YG, Guo X, Xu P et al (2005) Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clin Orthop 430:219–226PubMedGoogle Scholar
  85. 85.
    Zweig MH, Campbell G (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39:561–577PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • S. Rajasekaran
    • 1
  • K. Venkatadass
    • 1
  • J.  Naresh Babu
    • 1
  • K. Ganesh
    • 1
  • Ajoy P. Shetty
    • 1
  1. 1.Department of Orthopaedics and Spine SurgeryGanga HospitalCoimbatoreIndia

Personalised recommendations