Developments in intervertebral disc disease research: pathophysiology, mechanobiology, and therapeutics

  • Kathryn T. Weber
  • Timothy D. Jacobsen
  • Robert Maidhof
  • Justin Virojanapa
  • Chris Overby
  • Ona Bloom
  • Shaheda Quraishi
  • Mitchell Levine
  • Nadeen O. ChahineEmail author
Biological Adjuvants in Orthopedic Surgery (J Dines and D Grande, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Biological Adjuvants in Orthopedic Surgery


Low back pain is a leading cause of disability worldwide and the second most common cause of physician visits. There are many causes of back pain, and among them, disc herniation and intervertebral disc degeneration are the most common diagnoses and targets for intervention. Currently, clinical treatment outcomes are not strongly correlated with diagnoses, emphasizing the importance for characterizing more completely the mechanisms of degeneration and their relationships with symptoms. This review covers recent studies elucidating cellular and molecular changes associated with disc mechanobiology, as it relates to degeneration and regeneration. Specifically, we review findings on the biochemical changes in disc diseases, including cytokines, chemokines, and proteases; advancements in disc disease diagnostics using imaging modalities; updates on studies examining the response of the intervertebral disc to injury; and recent developments in repair strategies, including cell-based repair, biomaterials, and tissue engineering. Findings on the effects of the omega-6 fatty acid, linoleic acid, on nucleus pulposus tissue engineering are presented. Studies described in this review provide greater insights into the pathogenesis of disc degeneration and may define new paradigms for early or differential diagnostics of degeneration using new techniques such as systemic biomarkers. In addition, research on the mechanobiology of disease enriches the development of therapeutics for disc repair, with potential to diminish pain and disability associated with disc degeneration.


Spine Intervertebral disc Back pain Inflammation Tissue engineering Stem cells Biomaterials 


Compliance with Ethics Guidelines

Conflict of Interest

Kathryn T. Weber, Timothy D. Jacobsen, Robert Maidhof, Justin Virojanapa, Chris Overby, Ona Bloom, Shaheda Quraishi, and Mitchell Levine declare that they have no conflict of interest.

Nadeen Chahine reports grants from National Science Foundation (NSF CAREER 1151605), grants from New York State Department of Health (Empire Clinical Research Investigator Program), grants from National Institute of Health (R41AG050021), and grants from American Orthopedic Society for Sports Medicine, during the conduct of the study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance

  1. 1.
    ConnellyL.B, Woolf A, and Brooks P. Cost-effectiveness of interventions for musculoskeletal conditions. 2006.Google Scholar
  2. 2.
    Hoy D, Bain C, Williams G, March L, Brooks P, Blyth F, et al. A systematic review of the global prevalence of low back pain. Arthritis Rheum. 2012;64(6):2028–37.PubMedGoogle Scholar
  3. 3.
    Pleis JR, Ward BW, Lucas JW. Summary health statistics for U.S. adults: national health interview survey. Vital Health Stat. 2009;10(249):1–207.Google Scholar
  4. 4.
    Smitherman TA, Burch R, Sheikh H, Loder E. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache. 2013;53(3):427–36.PubMedGoogle Scholar
  5. 5.
    Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J. 2008;8(1):8–20.PubMedGoogle Scholar
  6. 6.
    Initiative, U.S.B.a.J. Health care utilization and economic cost of musculoskeletal disease, In The burden of musculoskeletal diseases in the United States, A.A.o.O. Surgeons, Editor. 2011.Google Scholar
  7. 7.
    Katz JN. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J Bone Joint Surg Am. 2006;88 Suppl 2:21–4.PubMedGoogle Scholar
  8. 8.
    Deyo RA, Weinstein JN. Low back pain. N Engl J Med. 2001;344(5):363–70.PubMedGoogle Scholar
  9. 9.
    Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976). 2006;31(18):2151–61.Google Scholar
  10. 10.
    Boden SD, McCowin PR, Davis DO, Dina TS, Mark AS, Wiesel S. Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am. 1990;72(8):1178–84.PubMedGoogle Scholar
  11. 11.
    Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med. 1994;331(2):69–73.PubMedGoogle Scholar
  12. 12.
    Takatalo J, Karppinen J, Niinimaki J, Taimela S, Nayha S, Mutanen P, et al. Does lumbar disc degeneration on magnetic resonance imaging associate with low back symptom severity in young Finnish adults? Spine (Phila Pa 1976). 2011;36(25):2180–9.Google Scholar
  13. 13.
    Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain. Spine (Phila Pa 1976). 2007;32(7):816–23.Google Scholar
  14. 14.
    DeVine J, Norvell DC, Ecker E, Fourney DR, Vaccaro A, Wang J, et al. Evaluating the correlation and responsiveness of patient-reported pain with function and quality-of-life outcomes after spine surgery. Spine (Phila Pa 1976). 2011;36(21 Suppl):S69–74.Google Scholar
  15. 15.
    Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, et al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest. 1996;98(4):996–1003.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Ohshima H, Tsuji H, Hirano N, Ishihara H, Katoh Y, Yamada H. Water diffusion pathway, swelling pressure, and biomechanical properties of the intervertebral disc during compression load. Spine (Phila Pa 1976). 1989;14(11):1234–44.Google Scholar
  17. 17.
    Mwale F, Iatridis JC, Antoniou J. Quantitative MRI as a diagnostic tool of intervertebral disc matrix composition and integrity. Eur Spine J. 2008;17 Suppl 4:432–40.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Iatridis JC, Nicoll SB, Michalek AJ, Walter BA, Gupta MS. Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? Spine J. 2013;13(3):243–62.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Guinto Jr FC, Hashim H, Stumer M. CT demonstration of disk regression after conservative therapy. AJNR Am J Neuroradiol. 1984;5(5):632–3.PubMedGoogle Scholar
  20. 20.
    Keskil S, Ayberk G, Evliyaoglu C, Kizartici T, Yucel E, Anbarci H. Spontaneous resolution of “protruded” lumbar discs. Minim Invasive Neurosurg. 2004;47(4):226–9.PubMedGoogle Scholar
  21. 21.
    Hasue M, Fujiwara M. Epidemiologic and clinical studies of long-term prognosis of low-back pain and sciatica. Spine (Phila Pa 1976). 1979;4(2):150–5.Google Scholar
  22. 22.
    Komori H, Shinomiya K, Nakai O, Yamaura I, Takeda S, Furuya K. The natural history of herniated nucleus pulposus with radiculopathy. Spine (Phila Pa 1976). 1996;21(2):225–9.Google Scholar
  23. 23.
    Benyamin RM, Manchikanti L, Parr AT, Diwan S, Singh V, Falco FJ, et al. The effectiveness of lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain. Pain Physician. 2012;15(4):E363–404.PubMedGoogle Scholar
  24. 24.
    Manchikanti L, Buenaventura RM, Manchikanti KN, Ruan X, Gupta S, Smith HS, et al. Effectiveness of therapeutic lumbar transforaminal epidural steroid injections in managing lumbar spinal pain. Pain Physician. 2012;15(3):E199–245.PubMedGoogle Scholar
  25. 25.
    Friedly JL, Comstock BA, Turner JA, Heagerty PJ, Deyo RA, Sullivan SD, et al. A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med. 2014;371(1):11–21.PubMedGoogle Scholar
  26. 26.
    Benyamin RM, Manchikanti L, Parr AT, Diwan S, Singh V, Falco FJ, et al. The effectiveness of lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain. Pain Physician. 2012;15(4):E363–404.PubMedGoogle Scholar
  27. 27.
    Gibson JN, Waddell G. Surgical interventions for lumbar disc prolapse. Cochrane Database Syst Rev. 2007;2:CD001350.PubMedGoogle Scholar
  28. 28.
    Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA. A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate. Spine (Phila Pa 1976). 2003;28(12):1219–24. discussion 1225.Google Scholar
  29. 29.
    Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002;27(21):2396–408.Google Scholar
  30. 30.
    Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013;158(12):890–902.PubMedGoogle Scholar
  31. 31.
    Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. 2013;158(12):877–89.PubMedGoogle Scholar
  32. 32.
    Walker B, Koerner J, Sankarayanaryanan S, and Radcliff K, A consensus statement regarding the utilization of BMP in spine surgery. Curr Rev Musculoskelet Med.Google Scholar
  33. 33.••
    Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2013;10(1):44–56. This paper reviews the contribution of cytokines and immune cells to catabolic, angiogenic and nociceptive processes in disc diseases.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289–96.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Rajan NE, Bloom O, Maidhof R, Stetson N, Sherry B, Levine M, et al. Toll-like receptor 4 (TLR4) expression and stimulation in a model of intervertebral disc inflammation and degeneration. Spine (Phila Pa 1976). 2012;38(16):1343–51.Google Scholar
  36. 36.
    Klawitter M, Hakozaki M, Kobayashi H, Krupkova O, Quero L, Ospelt C, Gay S, Hausmann O, Liebscher T, Meier U, Sekiguchi M, Konno SI, Boos N, Ferguson SJ, and Wuertz . Expression and regulation of Toll-like receptors (TLRs) in human intervertebral disc cells. Eur Spine J.Google Scholar
  37. 37.
    Capossela S, Schlafli P, Bertolo A, Janner T, Stadler BM, Potzel T, et al. Degenerated human intervertebral discs contain autoantibodies against extracellular matrix proteins. Eur Cell Mater. 2014;27:251–63. discussion 263.PubMedGoogle Scholar
  38. 38.
    Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Norton HJ, Hanley Jr EN. Production and expression of RANTES (CCL5) by human disc cells and modulation by IL-1-beta and TNF-alpha in 3D culture. Exp Mol Pathol. 2014;96(2):133–8.PubMedGoogle Scholar
  39. 39.
    Le Maitre CL, Freemont AJ, Hoyland JA. Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells. Arthritis Res Ther. 2009;11(5):R137.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Walsh AJ, Bradford DS, Lotz JC. In vivo growth factor treatment of degenerated intervertebral discs. Spine (Phila Pa 1976). 2004;29(2):156–63.Google Scholar
  41. 41.
    Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Hanley Jr EN. Growth and differentiation factor-5 (GDF-5) in the human intervertebral annulus cells and its modulation by IL-1ss and TNF-alpha in vitro. Exp Mol Pathol. 2014;96(2):225–9.PubMedGoogle Scholar
  42. 42.
    Bachmeier BE, Nerlich A, Mittermaier N, Weiler C, Lumenta C, Wuertz K, et al. Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur Spine J. 2009;18(11):1573–86.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Zigouris A, Batistatou A, Alexiou GA, Pachatouridis D, Mihos E, Drosos D, et al. Correlation of matrix metalloproteinases-1 and -3 with patient age and grade of lumbar disc herniation. J Neurosurg Spine. 2011;14(2):268–72.PubMedGoogle Scholar
  44. 44.
    Canbay S, Turhan N, Bozkurt M, Arda K, Caglar S. Correlation of matrix metalloproteinase-3 expression with patient age, magnetic resonance imaging and histopathological grade in lumbar disc degeneration. Turk Neurosurg. 2013;23(4):427–33.PubMedGoogle Scholar
  45. 45.
    Rastogi A, Kim H, Twomey JD, Hsieh AH. MMP-2 mediates local degradation and remodeling of collagen by annulus fibrosus cells of the intervertebral disc. Arthritis Res Ther. 2013;15(2):R57.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Furtwangler T, Chan SC, Bahrenberg G, Richards PJ, Gantenbein-Ritter B. Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine (Phila Pa 1976). 2013;38(22):E1377–87.Google Scholar
  47. 47.
    Albert HB, Lambert P, Rollason J, Sorensen JS, Worthington T, Pedersen MB, et al. Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur Spine J. 2013;22(4):690–6.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Modic MT, Steinberg PM, Ross JS, Masaryk TJ, Carter JR. Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology. 1988;166(1 Pt 1):193–9.PubMedGoogle Scholar
  49. 49.
    Jensen TS, Karppinen J, Sorensen JS, Niinimaki J, Leboeuf-Yde C. Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain. Eur Spine J. 2008;17(11):1407–22.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Bekyarova GY, Ivanova DG, Madjova VH. Molecular mechanisms associating oxidative stress with endothelial dysfunction in the development of various vascular complications in diabetes mellitus. Folia Med (Plovdiv). 2007;49(3–4):13–9.Google Scholar
  51. 51.
    Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract. 2013;7(5):e330–41.PubMedGoogle Scholar
  52. 52.
    Tsai TT, Ho NY, Lin YT, Lai PL, Fu TS, Niu CC, et al. Advanced glycation end products in degenerative nucleus pulposus with diabetes. J Orthop Res. 2013;32(2):238–44.PubMedGoogle Scholar
  53. 53.
    Garg A, Hegmann KT, Moore JS, Kapellusch J, Thiese MS, Boda S, et al. Study protocol title: a prospective cohort study of low back pain. BMC Musculoskelet Disord. 2013;14:84.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Illien-Junger S, Grosjean F, Laudier DM, Vlassara H, Striker GE, Iatridis JC. Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes. PLoS One. 2013;8(5):e64302.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Ohtori S, Miyagi M, Eguchi Y, Inoue G, Orita S, Ochiai N, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976). 2012;37(6):439–44.Google Scholar
  56. 56.
    Cohen SP, Bogduk N, Dragovich A, Buckenmaier 3rd CC, Griffith S, Kurihara C, et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology. 2009;110(5):1116–26.PubMedGoogle Scholar
  57. 57.
    Okoro T, Tafazal SI, Longworth S, Sell PJ. Tumor necrosis alpha-blocking agent (etanercept): a triple blind randomized controlled trial of its use in treatment of sciatica. J Spinal Disord Tech. 2010;23(1):74–7.PubMedGoogle Scholar
  58. 58.
    Cohen SP, White RL, Kurihara C, Larkin TM, Chang A, Griffith SR, et al. Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann Intern Med. 2012;156(8):551–9.PubMedGoogle Scholar
  59. 59.
    Genevay S, Stingelin S, Gabay C. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Ann Rheum Dis. 2004;63(9):1120–3.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Genevay S, Finckh A, Zufferey P, Viatte S, Balague F, Gabay C. Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial. Ann Rheum Dis. 2012;71(4):560–2.PubMedGoogle Scholar
  61. 61.
    Genevay S, Viatte S, Finckh A, Zufferey P, Balague F, Gabay C. Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(8):2339–46.PubMedGoogle Scholar
  62. 62.
    Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA, Bowman C, et al. The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine (Phila Pa 1976). 2006;31(24):2759–66.Google Scholar
  63. 63.
    Williams NH, Lewis R, Din NU, Matar HE, Fitzsimmons D, Phillips CJ, et al. A systematic review and meta-analysis of biological treatments targeting tumour necrosis factor alpha for sciatica. Eur Spine J. 2013;22(9):1921–35.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Jacobs L, Vo N, Coehlo JP, Dong Q, Bechara B, Woods B, Hempen E, Hartman R, Preuss H, Balk J, Kang J, and Sowa G. Glucosamine supplementation demonstrates a negative effect on intervertebral disc matrix in an animal model of disc degeneration. Spine (Phila Pa 1976), 2013.Google Scholar
  65. 65.
    Sowa GA, Coelho JP, Jacobs LJ, Komperda K, Sherry N, Vo NV, Preuss HG, Balk JL, and Kang JD. The effects of glucosamine sulfate on intervertebral disc annulus fibrosus cells in vitro. Spine J. 2013Google Scholar
  66. 66.
    Cortes DH, Jacobs NT, DeLucca JF, Elliott DM. Elastic, permeability and swelling properties of human intervertebral disc tissues: a benchmark for tissue engineering. J Biomech. 2014;47(9):2088–94.PubMedGoogle Scholar
  67. 67.
    Huang J, Yan H, Jian F, Wang X, and Li H. Numerical analysis of the influence of nucleus pulposus removal on the biomechanical behavior of a lumbar motion segment. Comput Methods Biomech Biomed Engin: p. 1–9.Google Scholar
  68. 68.
    Antoniou J, Epure LM, Michalek AJ, Grant MP, Iatridis JC, Mwale F. Analysis of quantitative magnetic resonance imaging and biomechanical parameters on human discs with different grades of degeneration. J Magn Reson Imaging. 2013;38(6):1402–14.PubMedGoogle Scholar
  69. 69.
    Ellingson AM, Mehta H, Polly DW, Ellermann J, Nuckley DJ. Disc degeneration assessed by quantitative T2* (T2 star) correlated with functional lumbar mechanics. Spine (Phila Pa 1976). 2013;38(24):E1533–40.Google Scholar
  70. 70.•
    Cortes DH, Magland JF, Wright AC, Elliott DM. The shear modulus of the nucleus pulposus measured using magnetic resonance elastography: a potential biomarker for intervertebral disc degeneration. Magn Reson Med. 2014;72(1):211–9. This paper demonstrates a new imaging tool for disc diagnostics using magnetic resonance elastography.PubMedGoogle Scholar
  71. 71.
    Jackman TM, Hussein AI, Adams AM, Makhnejia KK, Morgan EF. Endplate deflection is a defining feature of vertebral fracture and is associated with properties of the underlying trabecular bone. J Orthop Res. 2014;32(7):880–6.PubMedGoogle Scholar
  72. 72.
    Yamaguchi T, Inoue N, Sah RL, Lee YP, Taborek AP, Williams GM, et al. Micro-computed tomography-based three-dimensional kinematic analysis during lateral bending for spinal fusion assessment in a rat posterolateral lumbar fusion model. Tissue Eng Part C Methods. 2014;20(7):578–87.PubMedGoogle Scholar
  73. 73.
    Jaumard NV, Welch WC, Winkelstein BA. Spinal facet joint biomechanics and mechanotransduction in normal, injury and degenerative conditions. J Biomech Eng. 2011;133(7):071010.PubMedGoogle Scholar
  74. 74.
    Igarashi A, Kikuchi S, Konno S. Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders. J Orthop Sci. 2007;12(2):154–60.PubMedGoogle Scholar
  75. 75.
    Alipui DO, Chen D, Houseman C, Stetson N, Black K, Overby C, Levine M, and Chahine N. Molecular Profiles of Degenerative Biomarkers in the ligamentum flavum and their relationships with disc disease severity. In Transactions of the Orthopedics Research Society. 2014. New Orleans, LA.Google Scholar
  76. 76.
    Dudli S, Ferguson SJ, Haschtmann D. Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury. Spine J. 2014;14(7):1256–64.PubMedGoogle Scholar
  77. 77.
    Dudli S, Haschtmann D, Ferguson SJ. Fracture of the vertebral endplates, but not equienergetic impact load, promotes disc degeneration in vitro. J Orthop Res. 2012;30(5):809–16.PubMedGoogle Scholar
  78. 78.
    Gregory DE, Bae WC, Sah RL, Masuda K. Disc degeneration reduces the delamination strength of the annulus fibrosus in the rabbit annular disc puncture model. Spine J. 2014;14(7):1265–71.PubMedGoogle Scholar
  79. 79.
    Neidlinger-Wilke C, Boldt A, Brochhausen C, Galbusera F, Carstens C, Copf F, et al. Molecular interactions between human cartilaginous endplates and nucleus pulposus cells: a preliminary investigation. Spine (Phila Pa 1976). 2014;39(17):1355–64.Google Scholar
  80. 80.
    Fernando HN, Czamanski J, Yuan TY, Gu W, Salahadin A, Huang CY. Mechanical loading affects the energy metabolism of intervertebral disc cells. J Orthop Res. 2011;29(11):1634–41.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Salvatierra JC, Yuan TY, Fernando H, Castillo A, Gu WY, Cheung HS, et al. Difference in energy metabolism of annulus fibrosus and nucleus pulposus cells of the intervertebral disc. Cell Mol Bioeng. 2011;4(2):302–10.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Li S, Jia X, Duance VC, Blain EJ. The effects of cyclic tensile strain on the organisation and expression of cytoskeletal elements in bovine intervertebral disc cells: an in vitro study. Eur Cell Mater. 2011;21:508–22.PubMedGoogle Scholar
  83. 83.
    Chan SC, Walser J, Kappeli P, Shamsollahi MJ, Ferguson SJ, Gantenbein-Ritter B. Region specific response of intervertebral disc cells to complex dynamic loading: an organ culture study using a dynamic torsion-compression bioreactor. PLoS One. 2013;8(8):e72489.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Cho H, Seth A, Warmbold J, Robertson JT, Hasty KA. Aging affects response to cyclic tensile stretch: paradigm for intervertebral disc degeneration. Eur Cell Mater. 2011;22:137–45. discussion 145–6.PubMedGoogle Scholar
  85. 85.
    Maidhof R, Jacobsen T, Papatheodorou A, Chahine NO. Inflammation induces irreversible biophysical changes in isolated nucleus pulposus cells. PLoS One. 2014;9(6):e99621.PubMedCentralPubMedGoogle Scholar
  86. 86.•
    Hwang PY, Chen J, Jing L, Hoffman BD, Setton LA. The role of extracellular matrix elasticity and composition in regulating the nucleus pulposus cell phenotype in the intervertebral disc: a narrative review. J Biomech Eng. 2014;136(2):021010. This paper reviews the complex mechanobiology of the disc, highlighting the effects of cell-matrix interactions and susbtrate stiffness in the cellular microenvironment.PubMedGoogle Scholar
  87. 87.
    de Souza Grava AL, Ferrari LF, Defino HL. Cytokine inhibition and time-related influence of inflammatory stimuli on the hyperalgesia induced by the nucleus pulposus. Eur Spine J. 2012;21(3):537–45.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Kartha S, Zeeman ME, Baig HA, Guarino BB, and Winkelstein BA. Upregulation of BDNF & NGF in cervical intervertebral discs exposed to painful whole body vibration. Spine (Phila Pa 1976).Google Scholar
  89. 89.
    Moon HJ, Yurube T, Lozito TP, Pohl P, Hartman RA, Sowa GA, et al. Effects of secreted factors in culture medium of annulus fibrosus cells on microvascular endothelial cells: elucidating the possible pathomechanisms of matrix degradation and nerve in-growth in disc degeneration. Osteoarthritis Cartilage. 2014;22(2):344–54.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Gao R, Brigstock DR. Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha (v) beta (3) and heparan sulfate proteoglycan. J Biol Chem. 2004;279(10):8848–55.PubMedGoogle Scholar
  91. 91.
    Tran CM, Markova D, Smith HE, Susarla B, Ponnappan RK, Anderson DG, et al. Regulation of CCN2/connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: role of Smad and activator protein 1 signaling. Arthritis Rheum. 2010;62(7):1983–92.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tran CM, Schoepflin ZR, Markova DZ, Kepler CK, Anderson DG, Shapiro IM, et al. CCN2 suppresses catabolic effects of interleukin-1beta through alpha5beta1 and alphaVbeta3 integrins in nucleus pulposus cells: implications in intervertebral disc degeneration. J Biol Chem. 2014;289(11):7374–87.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, et al. Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-kappaB inhibition via HGF. J Cell Physiol. 2010;225(3):757–66.PubMedGoogle Scholar
  94. 94.
    van Buul GM, Koevoet WL, Kops N, Bos PK, Verhaar JA, Weinans H, et al. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med. 2011;39(11):2362–70.PubMedGoogle Scholar
  95. 95.
    Kim HJ, Yeom JS, Koh YG, Yeo JE, Kang KT, Kang YM, et al. Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-alpha and IL-1. J Orthop Res. 2014;32(4):551–6.PubMedGoogle Scholar
  96. 96.
    Haschtmann D, Ferguson SJ, Stoyanov JV. BMP-2 and TGF-beta3 do not prevent spontaneous degeneration in rabbit disc explants but induce ossification of the annulus fibrosus. Eur Spine J. 2012;21(9):1724–33.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Osada R, Ohshima H, Ishihara H, Yudoh K, Sakai K, Matsui H, et al. Autocrine/paracrine mechanism of insulin-like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs. J Orthop Res. 1996;14(5):690–9.PubMedGoogle Scholar
  98. 98.
    Huang CY, Travascio F, Gu WY. Quantitative analysis of exogenous IGF-1 administration of intervertebral disc through intradiscal injection. J Biomech. 2012;45(7):1149–55.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Aoyama E, Hattori T, Hoshijima M, Araki D, Nishida T, Kubota S, et al. N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan. Biochem J. 2009;420(3):413–20.PubMedGoogle Scholar
  100. 100.
    Madiraju P, Gawri R, Wang H, Antoniou J, Mwale F. Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells. Eur Cell Mater. 2013;25:268–83.PubMedGoogle Scholar
  101. 101.
    Lee CS, Szczesny SE, Soslowsky LJ. Remodeling and repair of orthopedic tissue: role of mechanical loading and biologics: part II: cartilage and bone. Am J Orthop (Belle Mead NJ). 2011;40(3):122–8.Google Scholar
  102. 102.
    Mwale F, Roughley P, Antoniou J. Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. Eur Cell Mater. 2004;8:58–63. discussion 63–4.PubMedGoogle Scholar
  103. 103.
    Shen CL, Dunn DM, Henry JH, Li Y, Watkins BA. Decreased production of inflammatory mediators in human osteoarthritic chondrocytes by conjugated linoleic acids. Lipids. 2004;39(2):161–6.PubMedGoogle Scholar
  104. 104.
    Byers BA, Mauck RL, Chiang IE, Tuan RS. Transient exposure to transforming growth factor beta 3 under serum-free conditions enhances the biomechanical and biochemical maturation of tissue-engineered cartilage. Tissue Eng Part A. 2008;14(11):1821–34.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Lima EG, Bian L, Ng KW, Mauck RL, Byers BA, Tuan RS, et al. The beneficial effect of delayed compressive loading on tissue-engineered cartilage constructs cultured with TGF-beta3. Osteoarthritis Cartilage. 2007;15(9):1025–33.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Reza AT, Nicoll SB. Serum-free, chemically defined medium with TGF-beta (3) enhances functional properties of nucleus pulposus cell-laden carboxymethylcellulose hydrogel constructs. Biotechnol Bioeng. 2010;105(2):384–95.PubMedGoogle Scholar
  107. 107.
    Smith LJ, Chiaro JA, Nerurkar NL, Cortes DH, Horava SD, Hebela NM, et al. Nucleus pulposus cells synthesize a functional extracellular matrix and respond to inflammatory cytokine challenge following long-term agarose culture. Eur Cell Mater. 2011;22:291–301.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Smith AN, Muffley LA, Bell AN, Numhom S, Hocking AM. Unsaturated fatty acids induce mesenchymal stem cells to increase secretion of angiogenic mediators. J Cell Physiol. 2012;227(9):3225–33.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Kuelling FA, Foley KT, Liu JJ, Liebenberg E, Sin AH, Matsukawa A, et al. The anabolic effect of plasma-mediated ablation on the intervertebral disc: stimulation of proteoglycan and interleukin-8 production. Spine J. 2014;14(10):2479–87.PubMedGoogle Scholar
  110. 110.
    Chan SC, Burki A, Bonel HM, Benneker LM, Gantenbein-Ritter B. Papain-induced in vitro disc degeneration model for the study of injectable nucleus pulposus therapy. Spine J. 2013;13(3):273–83.PubMedGoogle Scholar
  111. 111.
    Tam V, Rogers I, Chan D, Leung VY, Cheung KM. A comparison of intravenous and intradiscal delivery of multipotential stem cells on the healing of injured intervertebral disk. J Orthop Res. 2014;32(6):819–25.PubMedGoogle Scholar
  112. 112.
    Leckie SK, Sowa GA, Bechara BP, Hartman RA, Coelho JP, Witt WT, et al. Injection of human umbilical tissue-derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo. Spine J. 2013;13(3):263–72.PubMedGoogle Scholar
  113. 113.
    Chen J, Lee EJ, Jing L, Christoforou N, Leong KW, Setton LA. Differentiation of mouse induced pluripotent stem cells (iPSCs) into nucleus pulposus-like cells in vitro. PLoS One. 2013;8(9):e75548.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Liu Y, Rahaman MN, Bal BS. Modulating notochordal differentiation of human induced pluripotent stem cells using natural nucleus pulposus tissue matrix. PLoS One. 2014;9(7):e100885.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Potier EK. Ito, Can notochordal cells promote bone marrow stromal cell potential for nucleus pulposus enrichment? A simplified in vitro system. Tissue Eng Part A.Google Scholar
  116. 116.
    Purmessur D, Cornejo MC, Cho SK, Hecht AC, Iatridis JC. Notochordal cell-derived therapeutic strategies for discogenic back pain. Glob Spine J. 2013;3(3):201–18.Google Scholar
  117. 117.
    Bucher C, Gazdhar A, Benneker LM, Geiser T, and Gantenbein-Ritter B. Nonviral gene delivery of growth and differentiation factor 5 to human mesenchymal stem cells injected into a 3D bovine intervertebral disc organ culture system. Stem Cells Int. 2013: p. 326828.Google Scholar
  118. 118.
    Allon AA, Butcher K, Schneider RA, Lotz JC. Structured bilaminar coculture outperforms stem cells and disc cells in a simulated degenerate disc environment. Spine (Phila Pa 1976). 2012;37(10):813–8.Google Scholar
  119. 119.
    Allon AA, Butcher K, Schneider RA, Lotz JC. Structured coculture of mesenchymal stem cells and disc cells enhances differentiation and proliferation. Cells Tissues Organs. 2012;196(2):99–106.PubMedCentralPubMedGoogle Scholar
  120. 120.
    MacBarb RF, Chen AL, Hu JC, Athanasiou KA. Engineering functional anisotropy in fibrocartilage neotissues. Biomaterials. 2013;34(38):9980–9.PubMedGoogle Scholar
  121. 121.
    Reitmaier S, Shirazi-Adl A, Bashkuev M, Wilke HJ, Gloria A, Schmidt H. In vitro and in silico investigations of disc nucleus replacement. J R Soc Interface. 2012;9(73):1869–79.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Leckie AE, Akens MK, Woodhouse KA, Yee AJ, Whyne CM. Evaluation of thiol-modified hyaluronan and elastin-like polypeptide composite augmentation in early-stage disc degeneration: comparing 2 minimally invasive techniques. Spine (Phila Pa 1976). 2012;37(20):E1296–303.Google Scholar
  123. 123.
    Reitmaier S, Wolfram U, Ignatius A, Wilke HJ, Gloria A, Martin-Martinez JM, et al. Hydrogels for nucleus replacement—facing the biomechanical challenge. J Mech Behav Biomed Mater. 2012;14:67–77.PubMedGoogle Scholar
  124. 124.
    Kranenburg HJ, Meij BP, Onis D, van der Veen AJ, Saralidze K, Smolders LA, et al. Design, synthesis, imaging, and biomechanics of a softness-gradient hydrogel nucleus pulposus prosthesis in a canine lumbar spine model. J Biomed Mater Res B Appl Biomater. 2012;100(8):2148–55.PubMedGoogle Scholar
  125. 125.
    Malhotra NR, Han WM, Beckstein J, Cloyd J, Chen W, Elliott DM. An injectable nucleus pulposus implant restores compressive range of motion in the ovine disc. Spine (Phila Pa 1976). 2012;37(18):E1099–105.Google Scholar
  126. 126.
    Ahlgren BD, Lui W, Herkowitz HN, Panjabi MM, Guiboux JP. Effect of anular repair on the healing strength of the intervertebral disc: a sheep model. Spine (Phila Pa 1976). 2000;25(17):2165–70.Google Scholar
  127. 127.
    Likhitpanichkul M, Dreischarf M, Illien-Junger S, Walter BA, Nukaga T, Long RG, et al. Fibrin-genipin adhesive hydrogel for annulus fibrosus repair: performance evaluation with large animal organ culture, in situ biomechanics, and in vivo degradation tests. Eur Cell Mater. 2014;28:25–38.PubMedGoogle Scholar
  128. 128.
    Pei BQ, Li H, Zhu G, Li DY, Fan YB, and Wu SQ. The application of fiber-reinforced materials in disc repair. Biomed Res Int. 2013: p. 714103.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Kathryn T. Weber
    • 1
  • Timothy D. Jacobsen
    • 1
  • Robert Maidhof
    • 1
  • Justin Virojanapa
    • 2
  • Chris Overby
    • 2
  • Ona Bloom
    • 1
    • 3
  • Shaheda Quraishi
    • 2
    • 3
  • Mitchell Levine
    • 2
  • Nadeen O. Chahine
    • 1
    • 2
    • 4
    Email author
  1. 1.Biomechanics and Bioengineering Lab, Center for Autoimmune and Musculoskeletal DiseasesThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of NeurosurgeryHofstra North Shore-LIJ School of MedicineManhassetUSA
  3. 3.Department of Physical Medicine and RehabilitationHofstra North Shore-LIJ School of MedicineManhassetUSA
  4. 4.Department of Molecular MedicineHofstra North Shore-LIJ School of MedicineManhassetUSA

Personalised recommendations