Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy

Until recently, material removed from the intervertebral disc (IVD) at surgery consisted either of ‘loose bodies’ from the centre of the IVD or discal tissue displaced (prolapsed) into the intervertebral root or spinal canals. This material is best regarded as a by‐product of disc degeneration and therefore not representative of the disease process itself. Recent advances in surgical techniques, particularly anterior fusion, in which large segments of the anterior part of the IVD are excised with the anatomical relationships between different components intact, have generated material that can be investigated with modern molecular and cell biological techniques. This is an important area of study because degeneration of the lumbar IVDs is associated, perhaps causally, with low back pain, one of the most common and debilitating conditions in the West. ‘Degeneration’ carries implications of inevitable progression of wear‐and‐tear associated conditions. Modern research on human IVD tissue has shown that this is far from the case and that disruption of the micro‐anatomy described as degeneration is an active process, regulated by locally produced molecules. The exciting consequence of this observation is the possibility of being able to inhibit or even reverse the processes of degeneration using targeted therapy. Copyright © 2002 John Wiley & Sons, Ltd.

[1]  W. B. Berg The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis , 1999, Zeitschrift für Rheumatologie.

[2]  T. Kakiuchi,et al.  Inflammatory Cytokines in the Herniated Disc of the Lumbar Spine , 1996, Spine.

[3]  S. Hukuda,et al.  Immunohistochemical Study of Matrix Metalloproteinase‐3 and Tissue Inhibitor of Metalloproteinase‐1 in Human Intervertebral Discs , 1996, Spine.

[4]  A. Rowan,et al.  The Regulation of MMPs and TIMPs in Cartilage Turnover , 1999, Annals of the New York Academy of Sciences.

[5]  James D. Kang,et al.  Herniated Cervical Intervertebral Discs Spontaneously Produce Matrix Metalloproteinases, Nitric Oxide, Interleukin‐6, and Prostaglandin E2 , 1995, Spine.

[6]  J. Taylor,et al.  Human intervertebral disc acid glycosaminoglycans. , 1992, Journal of anatomy.

[7]  A. Freemont,et al.  In situ zymographic localisation of type II collagen degrading activity in osteoarthritic human articular cartilage , 1999, Annals of the rheumatic diseases.

[8]  J. Jackson,et al.  Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. , 1997, The Journal of rheumatology.

[9]  M. Aebi,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. , 1996, The Journal of clinical investigation.

[10]  James D. Kang,et al.  Adenovirus‐Mediated Gene Transfer to Nucleus Pulposus Cells: Implications for the Treatment of Intervertebral Disc Degeneration , 1998, Spine.

[11]  Napoleone Ferrara,et al.  VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation , 1999, Nature Medicine.

[12]  J. Lotz,et al.  Compression-induced degeneration of the intervertebral disc: an in vivo mouse model and finite-element study. , 1998, Spine.

[13]  P. Korovessis,et al.  Evolution of disc degeneration in lumbar spine: a comparative histological study between herniated and postmortem retrieved disc specimens. , 1998, Journal of spinal disorders.

[14]  J. Oro,et al.  The Lumbar Spine and Back Pain. , 1994 .

[15]  T. Kikuchi,et al.  Matrix metalloproteinase-3 production by human degenerated intervertebral disc. , 1997, Journal of spinal disorders.

[16]  A. Freemont,et al.  End-Plate Displacement During Compression of Lumbar Vertebra-Disc-Vertebra Segments and the Mechanism of Failure , 1993, Spine.

[17]  T. Kikuchi,et al.  The role of interleukin-1 on proteoglycan metabolism of rabbit annulus fibrosus cells cultured in vitro. , 1988, Spine.

[18]  J. Taylor,et al.  The chemical morphology of age-related changes in human intervertebral disc glycosaminoglycans from cervical, thoracic and lumbar nucleus pulposus and annulus fibrosus. , 1994, Journal of anatomy.

[19]  T. Yasuma,et al.  The histology of lumbar intervertebral disc herniation. The significance of small blood vessels in the extruded tissue. , 1993, Spine.

[20]  J. Mort,et al.  Identification of human intervertebral disc stromelysin and its involvement in matrix degradation , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[21]  S. Roberts,et al.  Analysis of aging and degeneration of the human intervertebral disc. , 1999, Spine.

[22]  M. Jayson,et al.  Nerve ingrowth into diseased intervertebral disc in chronic back pain , 1997, The Lancet.

[23]  James D. Kang,et al.  Toward a Biochemical Understanding of Human Intervertebral Disc Degeneration and Herniation: Contributions of Nitric Oxide, Interleukins, Prostaglandin E2, and Matrix Metalloproteinases , 1997, Spine.

[24]  E. Thonar,et al.  Stimulation of hyaluronan metabolism by interleukin‐1α in human articular cartilage , 2000 .

[25]  H. Tsuji,et al.  Effects of Hydrostatic Pressure on Matrix Synthesis and Matrix Metalloproteinase Production in the Human Lumbar Intervertebral Disc , 1997, Spine.

[26]  R. Myers,et al.  Exogenous Tumor Necrosis Factor-Alpha Mimics Nucleus Pulposus-Induced Neuropathology: Molecular, Histologic, and Behavioral Comparisons in Rats , 2000, Spine.

[27]  A. Silman,et al.  Predictors of early improvement in low back pain amongst consulters to general practice: the influence of pre-morbid and episode-related factors , 1999, Pain.

[28]  E Viikari-Juntura,et al.  Low back pain in relation to lumbar disc degeneration. , 2000, Spine.

[29]  L G Gilbertson,et al.  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. , 1999, Spine.

[30]  M. Takigawa,et al.  Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1. , 1999, Journal of biochemistry.

[31]  T. Oegema,et al.  Identification of heterogeneous cell populations in normal human intervertebral disc. , 1995, Journal of anatomy.

[32]  K. Lam,et al.  Lumbar disc high-intensity zone: the value and significance of provocative discography in the determination of the discogenic pain source , 2000, European Spine Journal.

[33]  A. Freemont,et al.  Demonstration of estrogen receptor mRNA in bone using in situ reverse-transcriptase polymerase chain reaction. , 1997, Bone.

[34]  H E Gruber,et al.  Analysis of Aging and Degeneration of the Human Intervertebral Disc: Comparison of Surgical Specimens With Normal Controls , 1998, Spine.

[35]  H. Thoenen,et al.  Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve , 1987, Nature.

[36]  M. Revel,et al.  Sensitivity of Anulus Fibrosus Cells to Interleukin 1&bgr;: Comparison With Articular Chondrocytes , 2000, Spine.

[37]  S. Kokubun,et al.  Changes with Age in Proteoglycan Synthesis in Cells Cultured In Vitro From the Inner and Outer Rabbit Annulus Fibrosus: Responses to Interleukin-1 and Interleukin-1 Receptor Antagonist Protein , 2000, Spine.

[38]  A. Freemont,et al.  A method for immunofluorescent localization of oestrogen receptors in bone sections from an egg-laying poultry strain. , 1998, Avian pathology : journal of the W.V.P.A.

[39]  A. Freemont,et al.  Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific , 1997, Annals of the rheumatic diseases.

[40]  James D. Kang,et al.  Herniated Lumbar Intervertebral Discs Spontaneously Produce Matrix Metalloproteinases, Nitric Oxide, Interleukin-6, and Prostaglandin E2 , 1996, Spine.

[41]  B. Caterson,et al.  Matrix Metalloproteinases And Aggrecanase: Their Role in Disorders of the Human Intervertebral Disc , 2000, Spine.

[42]  M. McKeehen,et al.  Anterior lumbar fusion improves discogenic pain at levels of prior posterolateral fusion. , 2000, Spine.

[43]  R. Saura,et al.  Intervertebral disc cell apoptosis by nitric oxide: biological understanding of intervertebral disc degeneration. , 2000, The Kobe journal of medical sciences.

[44]  W. B. van den Berg The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis , 1999, Zeitschrift fur Rheumatologie.

[45]  J. Kellgren The anatomical source of back pain. , 1977, Rheumatology and rehabilitation.

[46]  L. Kauppila,et al.  Ingrowth of blood vessels in disc degeneration. Angiographic and histological studies of cadaveric spines. , 1995, The Journal of bone and joint surgery. American volume.