Skip to main content
SpringerLink
Log in

A histocytological and radiological overview of the natural history of intervertebral disk: from embryonic formation to age-related degeneration

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

Abstract

Purpose

To elucidate the natural history of intervertebral disk (IVD) and characterize its embryonic beginnings and age-related degeneration.

Methods

Coronal sections of embryonic (E13.5-neonatal) and postnatal (4–60-week-old) Sprague–Dawley rat IVD were stained by a series of histological stainings (hematoxylin and eosin, Alcian blue, Picrosirius red, Masson, Periodic acid–Schiff). Growth kinetics within embryonic IVD were evaluated by immunohistochemical staining of Ki67 and proliferating cell nuclear antigen. Postnatal maturation and degeneration of IVD were visualized on radiology by X-ray, CT, and MR imaging.

Results

During the formation of rat IVD, inner annulus fibrosus (AF) and cartilaginous endplate (CEP) shared similar cell density, extracellular matrix, and potential of growth kinetics; notochord provided increased and enlarged cytoplasmic vacuoles to generate nucleus pulposus (NP), part of which was retained within CEP. Postnatally, vacuolated notochord cells were reduced by devacuolation, while chondrocytic NP cells increased; cartilaginous layers of CEP were narrowed by vertebrae growth and secondary ossification; fibrotic portion of AF decreased as cartilaginous matrix accumulated and infiltrated outward. In aged and degenerated IVD, large longitudinal fissures were detected near the boundaries between inner and outer AF, whereas both reduced cellularity and accumulated cell clusters were evident within the dehydrated NP; only part of these histocytological changes could be reported on radiology.

Conclusions

By showing that the natural history of IVD is orchestrated by a dynamic histocytological regulation, our study may facilitate better understanding of the developmental defects, cellular heterogeneity, age-related degenerative mechanisms, and biological regeneration of IVD.

Graphical abstract

These slides can be retrieved under Electronic Supplementary Material.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Risbud MV, Shapiro IM (2014) Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10(1):44–56

    Article  CAS  PubMed  Google Scholar 

  2. Wang F, Shi R, Cai F, Wang YT, Wu XT (2015) Stem cell approaches to intervertebral disc regeneration: obstacles from the disc microenvironment. Stem Cells Dev 24(21):2479–2495

    Article  PubMed  Google Scholar 

  3. Wang F, Cai F, Shi R, Wang XH, Wu XT (2016) Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage 24(3):398–408

    Article  CAS  PubMed  Google Scholar 

  4. Vos T, Flaxman AD, Naghavi M, Lozano R et al (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2163–2196

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wu X, Zhuang S, Mao Z, Chen H (2006) Microendoscopic discectomy for lumbar disc herniation: surgical technique and outcome in 873 consecutive cases. Spine 31(23):2689–2694

    Article  PubMed  Google Scholar 

  6. Sinkemani A, Hong X, Gao ZX, Zhuang SY et al (2015) Outcomes of microendoscopic discectomy and percutaneous transforaminal endoscopic discectomy for the treatment of lumbar disc herniation: a comparative retrospective study. Asian Spine J 9(6):833–840

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wang K, Hong X, Zhou BY, Bao JP et al (2015) Evaluation of transforaminal endoscopic lumbar discectomy in the treatment of lumbar disc herniation. Int Orthop 39(8):1599–1604

    Article  PubMed  Google Scholar 

  8. Luk KD, Samartzis D (2015) Intervertebral disc “dysgeneration”. Spine J 15(9):1915–1918

    Article  PubMed  Google Scholar 

  9. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 26(17):1873–1878

    Article  CAS  PubMed  Google Scholar 

  10. Davies BM, Atkinson RA, Ludwinski F, Freemont AJ et al (2016) Qualitative grading of disc degeneration by magnetic resonance in the lumbar and cervical spine: lack of correlation with histology in surgical cases. Br J Neurosurg 30(4):414–421

    Article  CAS  PubMed  Google Scholar 

  11. Battie MC, Videman T, Levalahti E, Gill K, Kaprio J (2007) Heritability of low back pain and the role of disc degeneration. Pain 131(3):272–280

    Article  PubMed  Google Scholar 

  12. Samartzis D, Karppinen J, Mok F, Fong DY, Luk KD, Cheung KM (2011) A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status. J Bone Joint Surg Am 93(7):662–670

    Article  PubMed  Google Scholar 

  13. Cheung KM, Samartzis D, Karppinen J, Mok FP et al (2010) Intervertebral disc degeneration: new insights based on “skipped” level disc pathology. Arthritis Rheum 62(8):2392–2400

    Article  PubMed  Google Scholar 

  14. Cheung KM, Karppinen J, Chan D, Ho DW et al (2009) Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine 34(9):934–940

    Article  PubMed  Google Scholar 

  15. Scaal M (2016) Early development of the vertebral column. Semin Cell Dev Biol 49:83–91

    Article  PubMed  Google Scholar 

  16. Corallo D, Trapani V, Bonaldo P (2015) The notochord: structure and functions. Cell Mol Life Sci 72(16):2989–3008

    Article  CAS  PubMed  Google Scholar 

  17. Chan WC, Au TY, Tam V, Cheah KS, Chan D (2014) Coming together is a beginning: the making of an intervertebral disc. Birth Defects Res C Embryo Today 102(1):83–100

    Article  CAS  PubMed  Google Scholar 

  18. Rodrigues-Pinto R, Richardson SM, Hoyland JA (2014) An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration. Eur Spine J 23(9):1803–1814

    Article  PubMed  Google Scholar 

  19. Risbud MV, Shapiro IM (2011) Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr 21(1):29–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Risbud MV, Schaer TP, Shapiro IM (2010) Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord. Dev Dyn 239(8):2141–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fleming A, Keynes R, Tannahill D (2004) A central role for the notochord in vertebral patterning. Development 131(4):873–880

    Article  CAS  PubMed  Google Scholar 

  22. Bruggeman BJ, Maier JA, Mohiuddin YS, Powers R et al (2012) Avian intervertebral disc arises from rostral sclerotome and lacks a nucleus pulposus: implications for evolution of the vertebrate disc. Dev Dyn 241(4):675–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Beckett MC, Ralphs JR, Caterson B, Hayes AJ (2015) The transmembrane heparan sulphate proteoglycan syndecan-4 is involved in establishment of the lamellar structure of the annulus fibrosus of the intervertebral disc. Eur Cell Mater 30:69–88 (discussion 88)

    Article  CAS  PubMed  Google Scholar 

  24. Takahashi Y, Yasuhiko Y, Takahashi J, Takada S et al (2013) Metameric pattern of intervertebral disc/vertebral body is generated independently of Mesp2/Ripply-mediated rostro-caudal patterning of somites in the mouse embryo. Dev Biol 380(2):172–184

    Article  CAS  PubMed  Google Scholar 

  25. Adams MA, Dolan P (2012) Intervertebral disc degeneration: evidence for two distinct phenotypes. J Anat 221(6):497–506

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yin R, Lord EL, Cohen JR, Buser Z et al (2015) Distribution of Schmorl nodes in the lumbar spine and their relationship with lumbar disk degeneration and range of motion. Spine 40(1):E49–E53

    Article  PubMed  Google Scholar 

  27. Teraguchi M, Yoshimura N, Hashizume H, Muraki S et al (2015) The association of combination of disc degeneration, end plate signal change, and Schmorl node with low back pain in a large population study: the Wakayama Spine Study. Spine J 15(4):622–628

    Article  PubMed  Google Scholar 

  28. Walcott BP, Nahed BV, Mohyeldin A, Coumans JV, Kahle KT, Ferreira MJ (2012) Chordoma: current concepts, management, and future directions. Lancet Oncol 13(2):e69–e76

    Article  PubMed  Google Scholar 

  29. Choi KS, Harfe BD (2011) Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs. Proc Natl Acad Sci U S A 108(23):9484–9489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stafford DA, Brunet LJ, Khokha MK, Economides AN, Harland RM (2011) Cooperative activity of noggin and gremlin 1 in axial skeleton development. Development 138(5):1005–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stafford DA, Monica SD, Harland RM (2014) Follistatin interacts with Noggin in the development of the axial skeleton. Mech Dev 131:78–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ellis K, Bagwell J, Bagnat M (2013) Notochord vacuoles are lysosome-related organelles that function in axis and spine morphogenesis. J Cell Biol 200(5):667–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Buisson N, Sirour C, Moreau N, Denker E et al (2014) An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis. Development 141(23):4569–4579

    Article  CAS  PubMed  Google Scholar 

  34. McMillen P, Holley SA (2015) The tissue mechanics of vertebrate body elongation and segmentation. Curr Opin Genet Dev 32:106–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gray RS, Wilm TP, Smith J, Bagnat M et al (2014) Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations. Dev Biol 386(1):72–85

    Article  CAS  PubMed  Google Scholar 

  36. Wilting J, Kurz H, Brand-Saberi B, Steding G et al (1994) Kinetics and differentiation of somite cells forming the vertebral column: studies on human and chick embryos. Anat Embryol (Berl) 190(6):573–581

    Article  CAS  Google Scholar 

  37. Li D, Yang H, Huang Y, Wu Y, Sun T, Li X (2014) Lumbar intervertebral disc puncture under C-arm fluoroscopy: a new rat model of lumbar intervertebral disc degeneration. Exp Anim 63(2):227–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sakai D, Nishimura K, Tanaka M, Nakajima D et al (2015) Migration of bone marrow-derived cells for endogenous repair in a new tail-looping disc degeneration model in the mouse: a pilot study. Spine J 15(6):1356–1365

    Article  PubMed  Google Scholar 

  39. Kim KW, Kim YS, Ha KY, Woo YK et al (2009) An autocrine or paracrine Fas-mediated counterattack: a potential mechanism for apoptosis of notochordal cells in intact rat nucleus pulposus. Spine 30(11):1247–1251

    Article  Google Scholar 

  40. Kim KW, Ha KY, Lee JS, Nam SW et al (2009) Notochordal cells stimulate migration of cartilage end plate chondrocytes of the intervertebral disc in in vitro cell migration assays. Spine J 9(4):323–329

    Article  PubMed  Google Scholar 

  41. Kim KW, Lim TH, Kim JG, Jeong ST, Masuda K, An HS (2003) The origin of chondrocytes in the nucleus pulposus and histologic findings associated with the transition of a notochordal nucleus pulposus to a fibrocartilaginous nucleus pulposus in intact rabbit intervertebral discs. Spine 28(10):982–990

    PubMed  Google Scholar 

  42. Hunter CJ, Matyas JR, Duncan NA (2004) Cytomorphology of notochordal and chondrocytic cells from the nucleus pulposus: a species comparison. J Anat 205(5):357–362

    Article  PubMed  PubMed Central  Google Scholar 

  43. Thompson K, Moore S, Tang S, Wiet M, Purmessur D (2018) The chondrodystrophic dog: a clinically relevant intermediate-sized animal model for the study of intervertebral disc-associated spinal pain. JOR Spine 1(1):e1011

    Article  PubMed  PubMed Central  Google Scholar 

  44. Cai F, Wu XT, Xie XH, Wang F et al (2015) Evaluation of intervertebral disc regeneration with implantation of bone marrow mesenchymal stem cells (BMSCs) using quantitative T2 mapping: a study in rabbits. Int Orthop 39(1):149–159

    Article  PubMed  Google Scholar 

  45. Samartzis D, Borthakur A, Belfer I, Bow C et al (2015) Novel diagnostic and prognostic methods for disc degeneration and low back pain. Spine J 15(9):1919–1932

    Article  PubMed  PubMed Central  Google Scholar 

  46. Peng B, Hou S, Wu W, Zhang C, Yang Y (2006) The pathogenesis and clinical significance of a high-intensity zone (HIZ) of lumbar intervertebral disc on MR imaging in the patient with discogenic low back pain. Eur Spine J 15(5):583–587

    Article  PubMed  Google Scholar 

  47. Shi R, Wang F, Hong X, Wang YT et al (2015) The presence of stem cells in potential stem cell niches of the intervertebral disc region: an in vitro study on rats. Eur Spine J 24(11):2411–2424

    Article  PubMed  Google Scholar 

  48. Henriksson H, Thornemo M, Karlsson C, Hägg O et al (2009) Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species. Spine 34(21):2278–2287

    Article  PubMed  Google Scholar 

  49. Li Z, Peroglio M, Alini M, Grad S (2015) Potential and limitations of intervertebral disc endogenous repair. Curr Stem Cell Res Ther 10(4):329–338

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This study was supported by the National Natural Science Foundation of China (No. 81201423, No. 81272035, No. 81572170) and the Fundamental Research Funds of the Central Universities (No. 2242017K3DN06). The authors would like to acknowledge He-Ling Fu, Yuan Zheng, and Dan Bao, from the Animal Core facility of Nanjing Medical University, for their aids in radiological imaging and analysis.

Author information

Authors and Affiliations

  1. Department of Spine Surgery, Zhongda Hospital, School of Medicine, Southeast University, 87# Dingjiaqiao Road, Nanjing, 210009, China

    Feng Wang, Cong Zhang, Arjun Sinkemani, Rui Shi, Zhi-Yang Xie, Lu Chen, Lu Mao & Xiao-Tao Wu

  2. Surgery Research Center, School of Medicine, Southeast University, 87# Dingjiaqiao Road, Nanjing, 210009, China

    Feng Wang, Cong Zhang, Arjun Sinkemani, Rui Shi, Zhi-Yang Xie, Lu Chen, Lu Mao & Xiao-Tao Wu

Authors
  1. Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arjun Sinkemani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Yang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao-Tao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao-Tao Wu.

Ethics declarations

Conflict of interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 1786 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, F., Zhang, C., Sinkemani, A. et al. A histocytological and radiological overview of the natural history of intervertebral disk: from embryonic formation to age-related degeneration. Eur Spine J 28, 633–648 (2019). https://doi.org/10.1007/s00586-019-05903-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-019-05903-8

Keywords

Search

Navigation