II. Disc RegenerationMolecular pathogenic factors in symptomatic disc degeneration
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)
- et al.
The experience of back pain in young Australians
Man Ther
(2001) Low back disability. A syndrome of Western civilization
Neurosurg Clin N Am
(1991)- et al.
An overview of the incidences and costs of low back pain
Orthop Clin North Am
(1991) - et al.
Quantitative MR imaging of lumbar intervertebral disc and vertebral bodies: methodology, reproducibility, and preliminary results
Magn Reson Imaging
(1994) - et al.
Bony overgrowths and abnormal calcifications about the spine
Radiol Clin North Am
(1988) What are the age-related changes in the spine?
Baillieres Clin Rheumatol
(1998)Biochemistry of the intervertebral disc
Int Rev Connect Tissue Res
(1979)- et al.
Effects of nicotine on the intervertebral disc: an experimental study in rabbits
J Orthop Sci
(2001) - et al.
The effect of cyclic compression on the mechanical properties of the inter-vertebral disc: an in vivo study in a rat tail model
Clin Biomech (Bristol, Avon)
(2003) - et al.
Effect of dynamic hydrostatic pressure on rabbit intervertebral disc cells
J Orthop Res
(2003)
Collagen in the ageing human intervertebral disc: an increase in covalently bound fluorophores and chromophores
Biochim Biophys Acta
Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age
Tissue Cell
Low back pain: a twentieth century health care enigma
Spine
Diagnosis and treatment of discogenic low back pain
Orthop Rev
The relative contributions of the disc and zygoapophyseal joint in chronic low back pain
Spine
Pathology and pathogenesis of lumbar spondylosis and stenosis
Spine
Aging and degeneration of the human intervertebral disc
Spine
Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science
Spine
Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens
Spine
Tissue characterization of symptomatic and asymptomatic disc herniations by quantitative magnetic resonance imaging
J Orthop Res
Quantitative magnetic resonance imaging in the assessment of degenerative disc disease
Magn Reson Med
Intervertebral disk degeneration and back pain
The relationship between height, shape and histological changes in early degeneration of the lower lumbar discs
Eur Spine J
Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc
Spine
Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation
J Bone Joint Surg Am
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
Associations between back pain history and lumbar MRI findings
Spine
The distribution, determinants, and clinical correlates of vertebral osteophytosis: a population based survey
J Rheumatol
Nerve growth factor expression and innervation of the painful intervertebral disc
J Pathol
Immunohistologic study of the ruptured intervertebral disc of the lumbar spine
Spine
The development of the human intervertebral disc
The development and growth of the intervertebral disc
Edinburgh Med J
Observations on the prenatal development of the intervertebral disc in man
J Anat
Observations on the development of the human intervertebral column
J Anat
Observations on the postnatal structure of the intervertebral disc in man
J Anat
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
Untersuchungen uber die entwicklung des schadelgrundes
Intervertebral disk structure, composition, and mechanical function
Types I and II collagens in intervertebral disc. Interchanging radial distributions in annulus fibrosus
Biochem J
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
Mechanisms of age-related decline in insulin-like growth factor-I dependent proteoglycan synthesis in rat intervertebral disc cells
Spine
Nutrition of the intervertebral disc: solute transport and metabolism
Connect Tissue Res
Nutrition of the intervertebral disc: effect of fluid flow on solute transport
Clin Orthop
Intervertebral disc nutrition. Diffusion versus convection
Clin Orthop
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
Mechanism of intervertebral disc degeneration caused by nicotine in rabbits to explicate intervertebral disc disorders caused by smoking
Spine
Nutrition of the intervertebral disc: acute effects of cigarette smoking. An experimental animal study
Ups J Med Sci
Transport properties of the human cartilage endplate in relation to its composition and calcification
Spine
The effect of lactate and pH on proteoglycan and protein synthesis rates in the intervertebral disc
Spine
Cited by (122)
FOXO3-Activated HOTTIP Sequesters miR-615-3p away from COL2A1 to Mitigate Intervertebral Disc Degeneration
2024, American Journal of PathologyThe impact of matrix age on intervertebral disc regeneration
2022, Biomaterials AdvancesFundamentals of Intervertebral Disc Degeneration
2022, World NeurosurgeryIntervertebral disc ageing and degeneration: The antiapoptotic effect of oestrogen
2020, Ageing Research ReviewsCell and Gene Therapy for Spine Regeneration: Mammalian Protein Production Platforms for Overproduction of Therapeutic Proteins and Growth Factors
2020, Neurosurgery Clinics of North AmericaCitation 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
FDA device/drug status: not applicable.
Nothing of value received from a commercial entity related to this research.