Elsevier

The Spine Journal

Volume 5, Issue 6, Supplement, November–December 2005, Pages S260-S266
The Spine Journal

II. Disc Regeneration
Molecular pathogenic factors in symptomatic disc degeneration

https://doi.org/10.1016/j.spinee.2005.02.010Get rights and content

Abstract

Background context

Although symptomatic disc degeneration is thought to be the leading cause of chronic low back pain, no available biologic therapy is yet available to treat this highly prevalent condition.

Purpose

In this article, the cellular, biomechanical and molecular alterations that occur during disc degeneration are reviewed to provide a better understanding of this pathologic process.

Study design

The cellular and molecular aspects of disc degeneration are reviewed.

Methods

The available studies detailing the molecular and cellular changes during disc degeneration are reviewed in an effort to provide a basis for understanding the biologic strategies for disc repair.

Results

Disc degeneration begins early in life and involves a cascade of changes at the cellular and molecular level that results in degradation of the extracellular matrix of the disc, leading to biomechanical failure of this complex structure.

Conclusion

With a thorough understanding of the cellular and molecular events causing degeneration of the intervertebral disc, rational strategies for disc repair can be understood and evaluated. It appears that biologic disc repair will be feasible in the future although challenges remain in this blossoming field.

Introduction

Low back pain is an endemic problem in Western societies and is the cause of substantial disability [1], [2], [3]. Whether it is measured in dollars or lost productivity, the cost of low back–related disability is staggering. About 80% of the population will experience back pain at some point during their lives [1], [2], [3], [4], [5]. Although there are many causes of back pain, symptomatic intervertebral disc degeneration appears to be one of the most prevalent causes of chronic low back symptoms [6]. Unfortunately, all available therapies for disc-related low back pain, whether conservative or invasive, are currently targeted at obtaining symptomatic relief rather than repairing the underlying degenerative process. To improve the clinical results for patients with low back disability, many investigators are focused on developing therapies to slow, halt or reverse the degenerative process within the intervertebral disc.

Rational approaches to the problem of disc degeneration require a thorough understanding of the molecular events occurring during the degenerative process. This article details the histologic, biomechanical, cellular and molecular changes that occur during intervertebral disc degeneration. It is the goal of this article to familiarize the reader with the complexity of the degenerative process within the disc and to provide a basis to understand and analyze the various tissue repair strategies that are currently under investigation.

Section snippets

The degenerative process

Although the gross morphologic and biomechanical attributes of disc degeneration have long been known, only more recently have the molecular events of disc degeneration begun to be elucidated [7]. Tissue homeostasis within the disc requires a balance between the synthesis and degradation of matrix macromolecules (Table 1). This crucial biosynthetic balance becomes disrupted, leading to diminished synthesis of disc matrix proteins and increased expression of catabolic enzymes and inflammatory

Embryologic disc development

Development of the spine starts in the third week of gestation. Cells derived from the endodermal layer separate and form the notochord, the precursor of the axial skeleton. Mesenchymal cells condense around the notochord and segment into light and dark bands to form the vertebral bodies and intervertebral discs, respectively [25].

As the intervertebral disc develops, cells in the peripheral region of the disc arrange themselves in a lamellar fashion and differentiate into fibroblasts, forming

Disc structure and anatomy

The human spine contains 24 intervertebral discs, with significant variability in size and histologic appearance over the length of the spine. Each disc functions as a stress-dissipating organ, made up of the bony vertebral endplates, cartilaginous endplates, the fibrous anulus fibrosus and the gelatinous nucleus pulposus. The latter two structures have been histologically divided into four distinct regions, including the outer anulus, inner anulus, transition zone and nucleus pulposus. The

Aging effects

Separating the effects of disc aging from pathologic disc degeneration is not simple. In all humans, a change in the cellular population and extracellular matrix of the disc occurs with age. Aging also leads to diminished metabolic output from the remaining disc cells [35]. Growth factors critical to cell viability are known to decline with age or become functionless, leading to diminished metabolic output [36].

As the disc ages, the distinct gross structure of the nucleus pulposus changes from

Disc nutrition

The disc is the largest avascular organ in the body and has no direct blood supply to its central region [32]. Nutrient and waste exchange to cells in the central region of the disc, therefore, depend on diffusion through the vertebral end plates. Cells in the central regions of the human disc lie 6 to 8 mm from the nearest blood supply. Adjacent to the bony endplate, specialized capillaries make sharp loops in the specialized compact endplate bone. The bone of the endplate contains micropores

Disc biomechanics

Human intervertebral discs are specialized to allow erect posture. When healthy, the disc is able to withstand enormous loads, exceeding the failure strength of the surrounding bone. During heavy lifting, lumbar disc loads in excess of 17,000 Newtons (N) have been calculated [46]. The disc serves to dissipate loads within the spine, cushioning and dampening these high stresses on the osseous structures. To accomplish this, the incompressible gel of the nucleus pulposus transmits disc stresses

Genetic contributions to disc degeneration

Disc degeneration is a complex, multifactorial process involving both genetic and environmental stimuli. Early, progressive disc degeneration has been recognized as a genetic trait in several familial studies [56], [57], [58]. In a twin study, Sambrook et al. [59] identified genetic factors as producing the strongest influence on disc degeneration in both the cervical and the lumbar region of the spine.

Several specific genetic markers have been linked to disc degeneration, including alleles of

Matrix production

Matrix production by the cells within the disc must keep pace with matrix degradation for tissue homeostasis to be maintained. Unfortunately, the disc, especially the nucleus pulposus, appears to have a limited repair response as degeneration ensues. This finding is underscored best by the study of Cs-Szabo et al [66], who studied the RNA message level and protein content of 34 human lumbar discs for a variety of matrix proteins, including aggrecan, versican, biglycan, decorin and fibromodulin.

Cellular loss and apoptosis

The cellular population of the nucleus pulposus changes dramatically during early life. In infantile discs, approximately 2% of nucleus pulposus cells are necrotic, whereas more than 80% of these cells are absent by adulthood [67]. Loss of nucleus pulposus cells has been correlated with the onset of degeneration of the disc. Cell loss resulting from necrosis and apoptosis continues to occur throughout life and likely plays a significant role in the degenerative process [68].

Apoptotic-cell

Catabolic mediators

Degenerative discs produce a host of molecules capable of causing degenerative, catabolic and inflammatory events within the disc. These substances may be classified as proteolytic and degradative enzymes, oxygen free radicals, nitric oxide, interleukins and prostaglandins. Degradative enzymes active in the disc include cathepsin, lysozyme, aggrecanase and several MMPs [73], [74], [75], [76], [77], [78]. Higher degradative enzyme concentrations and elevated enzyme activity have been shown in

Degenerative debris accumulation

Disc macromolecules, including collagens, proteoglycans and fibronectins, are broken down by degradative enzymes and by nonenzymatic damage. However, in many cases the breakdown process is incomplete, leading to the accumulation of large, inactive fragments. In the absence of a resident macrophage cell population, these molecular fragments accumulate, forming lipoprotein complexes within the disc [79], [91], [92]. As degeneration ensues, matrix proteins undergo complex glycation reactions,

Summary

The intervertebral disc is a complex structure, capable of dissipating large mechanical loads in the spine while allowing motion of the intervertebral segments. With aging and degeneration, changes occur within the disc, leading to structural and functional decline of the tissue and, in some cases, spinal pain. Disc degeneration is a complex process, encompassing many degradative events. A thorough understanding of the molecular events occurring during disc degeneration is necessary as

References (99)

  • S.E. Hormel et al.

    Collagen in the ageing human intervertebral disc: an increase in covalently bound fluorophores and chromophores

    Biochim Biophys Acta

    (1991)
  • J.J. Trout et al.

    Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age

    Tissue Cell

    (1982)
  • G. Waddell

    Low back pain: a twentieth century health care enigma

    Spine

    (1996)
  • J.S. Fishgrund et al.

    Diagnosis and treatment of discogenic low back pain

    Orthop Rev

    (1993)
  • A.C. Schwarzer et al.

    The relative contributions of the disc and zygoapophyseal joint in chronic low back pain

    Spine

    (1994)
  • W.H. Kirkaldy-Willis et al.

    Pathology and pathogenesis of lumbar spondylosis and stenosis

    Spine

    (1978)
  • J.A. Buckwalter

    Aging and degeneration of the human intervertebral disc

    Spine

    (1995)
  • N. Boos et al.

    Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science

    Spine

    (2002)
  • MillerJ.A. et al.

    Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens

    Spine

    (1988)
  • N. Boos et al.

    Tissue characterization of symptomatic and asymptomatic disc herniations by quantitative magnetic resonance imaging

    J Orthop Res

    (1997)
  • J. Antoniou et al.

    Quantitative magnetic resonance imaging in the assessment of degenerative disc disease

    Magn Reson Med

    (1998)
  • J.A. Buckwalter et al.

    Intervertebral disk degeneration and back pain

  • U. Berlemann et al.

    The relationship between height, shape and histological changes in early degeneration of the lower lumbar discs

    Eur Spine J

    (1998)
  • J.P. Thompson et al.

    Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc

    Spine

    (1990)
  • S.D. Boden et al.

    Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation

    J Bone Joint Surg Am

    (1990)
  • D.G. Borenstein et al.

    The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study

    J Bone Joint Surg Am

    (2001)
  • T. Videman et al.

    Associations between back pain history and lumbar MRI findings

    Spine

    (2003)
  • T.W. O'Neill et al.

    The distribution, determinants, and clinical correlates of vertebral osteophytosis: a population based survey

    J Rheumatol

    (1999)
  • A.J. Freemont et al.

    Nerve growth factor expression and innervation of the painful intervertebral disc

    J Pathol

    (2002)
  • M. Doita et al.

    Immunohistologic study of the ruptured intervertebral disc of the lumbar spine

    Spine

    (1996)
  • J.R. Taylor et al.

    The development of the human intervertebral disc

  • R. Walmsley

    The development and growth of the intervertebral disc

    Edinburgh Med J

    (1953)
  • A. Peacock

    Observations on the prenatal development of the intervertebral disc in man

    J Anat

    (1951)
  • G.M. Wyburn

    Observations on the development of the human intervertebral column

    J Anat

    (1944)
  • A. Peacock

    Observations on the postnatal structure of the intervertebral disc in man

    J Anat

    (1952)
  • K.W. Kim et al.

    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

    (2003)
  • R. Virchow

    Untersuchungen uber die entwicklung des schadelgrundes

    (1857)
  • J.A. Buckwalter et al.

    Intervertebral disk structure, composition, and mechanical function

  • D.R. Eyre et al.

    Types I and II collagens in intervertebral disc. Interchanging radial distributions in annulus fibrosus

    Biochem J

    (1976)
  • J. Antoniou 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)
  • S. Okuda et al.

    Mechanisms of age-related decline in insulin-like growth factor-I dependent proteoglycan synthesis in rat intervertebral disc cells

    Spine

    (2001)
  • S. Holm et al.

    Nutrition of the intervertebral disc: solute transport and metabolism

    Connect Tissue Res

    (1981)
  • J.P. Urban et al.

    Nutrition of the intervertebral disc: effect of fluid flow on solute transport

    Clin Orthop

    (1982)
  • M.M. Katz et al.

    Intervertebral disc nutrition. Diffusion versus convection

    Clin Orthop

    (1986)
  • H.A. Horner et al.

    2001 Volvo Award Winner in Basic Science Studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc

    Spine

    (2001)
  • M. Iwahashi et al.

    Mechanism of intervertebral disc degeneration caused by nicotine in rabbits to explicate intervertebral disc disorders caused by smoking

    Spine

    (2002)
  • S. Holm et al.

    Nutrition of the intervertebral disc: acute effects of cigarette smoking. An experimental animal study

    Ups J Med Sci

    (1988)
  • S. Roberts et al.

    Transport properties of the human cartilage endplate in relation to its composition and calcification

    Spine

    (1996)
  • H. Ohshima et al.

    The effect of lactate and pH on proteoglycan and protein synthesis rates in the intervertebral disc

    Spine

    (1992)
  • Cited by (122)

    • Cell and Gene Therapy for Spine Regeneration: Mammalian Protein Production Platforms for Overproduction of Therapeutic Proteins and Growth Factors

      2020, Neurosurgery Clinics of North America
      Citation Excerpt :

      However, it is generally accepted that disc degeneration begins at the molecular level early in life, long before the appearance of any radiographic changes or pain symptoms. The degeneration involves a cascade of changes at the cellular and molecular level that results in degradation of the disc ECM, leading to biomechanical failure of this unique and complex structure.23 IVD degeneration is thought to occur where there is a loss of homeostatic balance with a predominantly catabolic metabolic profile.24

    View all citing articles on Scopus

    FDA device/drug status: not applicable.

    Nothing of value received from a commercial entity related to this research.

    View full text