What is Intervertebral Disc Degeneration, and What Causes It?

Michael A. Adams, PhD; Peter J. Roughley, PhD


Spine. 2006;31(18):2151-2161. 

In This Article

Interpretation: What is Disc Degeneration?

The aforementioned evidence shows that many different influences are at work in old and degenerating discs, including genetic inheritance, impaired metabolite transport, altered levels of enzyme activity, cell senescence and death, changes in matrix macromolecules and water content, structural failure, and neurovascular ingrowth. Is it possible to use one or more of these processes to define disc degeneration? To be useful, the definition should be unambiguous and easy to apply to the discs of living people. It should be distinguishable from the inevitable and physiologic processes of growth, aging, and adaptive remodeling. It should be clinically relevant in terms of dysfunction or pain, and it should be consistent with the normal usage of declining to a lower or worse stage of being.[99] An unfavorable genetic inheritance is present from birth, and yet disc degeneration becomes common only 40 years later, and then only in lower lumbar discs. This implies that genetic inheritance, including polymorphic variations in susceptibility genes, is only a risk factor for future environmentally triggered events and does not in itself constitute disc degeneration.

Inadequate metabolite transport appears to be an inevitable consequence of growth and probably has little direct clinical relevance because it mostly affects the nucleus pulposus, which is the region of degenerated discs that is loaded the least (Figure 3C) and has the fewest nerve endings. The fact that endplate damage leads to disc degeneration, even though it enhances metabolite transport into the disc,[13] suggests that structural damage has the decisive influence on the degenerative process. The animal models of disc degeneration described previously support this inference. Inadequate nutrition may predispose to disc degeneration by compromising a disc's ability to respond to increased loading, or injury.

Certain markers of altered cell metabolism, such as increased cytokine and MMP activity,[100,101] could be used as a definition. They are associated with structural defects in the disc,[27] but currently available markers are unable to differentiate degeneration from growth, adaptive remodeling, and healing. Logically, to suggest that cytokines or proteinases cause disc degeneration is equivalent to blaming war on soldiers! Cytokines and proteinases are merely agents of change, rather than causes. The very complexity of connective tissue metabolism suggests that degeneration could occur from a failure to regulate specific proteinase activities.[94,102] However, it could equally be argued that the redundancy inherent in such a complex system (cells can achieve a given effect by many different methods) ensures that the system is very robust.

Aging causes inevitable and progressive changes in disc matrix composition, which resemble changes in other aging collagenous tissues. Biochemical changes influence tissue stiffness and strength, and some degraded matrix molecules can impair disc cell metabolism.[103] In addition, some matrix changes are detectable in vivo using MRI, manifesting as a dark disc.[104] However, age-related changes in matrix composition are inevitable, start soon after birth,[36,39] and are unrelated to pain.[1] Age-related reductions in endplate vascularity and disc cell density[7] could simply reflect necessary adaptations to increased mechanical loading at the onset of ambulation, and reduced metabolite transport in a growing disc. The microstructural clefts and tears that appear increasingly during growth may possibly lead to more extensive disruption in later life, but so long as they remain small, they appear to have little effect on the internal mechanical function of the disc.[61] In addition, they affect all spinal levels to a similar extent, unlike macroscopic changes that occur mostly between L4 and S1.

Ingrowth of nerves and blood vessels is an important feature of structurally disrupted discs, and appears to be directly, though variably, associated with pain.[67] Ingrowth could be facilitated by the loss of hydrostatic pressure that characterizes internal regions of intact discs (Figure 3) and that would collapse hollow capillaries. Reduced proteoglycan content in old and degenerated discs may also facilitate the ingrowth of nerves and capillaries105 because aggrecan can inhibit their growth in vitro.[106,107] Whichever mechanism is favored, it is apparent that ingrowth of blood vessels and nerves is too late an event in disc degeneration to be useful as a defining characteristic.

This leaves structural failure as a candidate for defining disc degeneration. We suggest that certain manifestations of structural failure meet all of the aforementioned criteria. They are easily detected, unambiguous markers of impaired disc function that do not occur inevitably with increasing age, and that are more closely related to back pain and sciatica than any other feature of aging or degenerated discs. Structural failure is permanent because adult discs are incapable of repairing gross defects.

Furthermore, structural failure naturally progresses by physical and biologic mechanisms and, therefore, is a suitable marker for a degenerative process. Physically, damage to one part of a disc increases load-bearing by adjacent tissue, so the damage is likely to spread. This principle explains crack propagation in engineering materials and why peripheral rim tears in animal discs progress in toward the nucleus.[81] Similarly, pathologic radial bulging of a disc progresses because compressive forces act to collapse the bulging lamellae. Biologic mechanisms of progression depend on the fact that a healthy intervertebral disc equalizes pressure within it, whereas a disrupted disc shows high concentrations of compressive stress in the anulus, and a decompressed nucleus (Figures 3C, 8). Reduced nucleus pressure impairs proteoglycan synthesis,[108] so the aggrecan and water content of a decompressed nucleus would progressively decrease, which is the opposite of what is required to restore normal disc function.

Stress profiles from a cadaveric lumbar disc showing the distribution of compressive stress across the disc's sagittal midline, before and after fracture of the vertebral endplate. Endplate fracture reduces compressive stress in the anterior and central regions of the adjacent disc, and generates a stress concentration in the posterior anulus[35] (left).

Similarly, the high stress concentrations generated in the anulus after endplate damage would also be expected to inhibit matrix synthesis and increase production of MMPs.[109] Therefore, in both regions of the disc, cells would behave inappropriately because structural disruption has uncoupled their local mechanical environment from the overall loading of the disc. Like a collapsed house, a disrupted disc can no longer perform its function, even though its constituent parts remain. Cellular attempts at repair become futile, not because the cells are deficient, but because their local mechanical environment has become abnormal. In this way, structural disruption of the disc progresses by physical and biologic methods, and the process represents degeneration rather than healing.

Defining disc degeneration in terms of structural failure allows all other features of degenerated discs to be considered as predisposing factors for, or consequences of, the disruption. Genetic inheritance and impaired metabolite transport make the disc matrix physically weaker and, so, more vulnerable to injury; so too can age-related changes in collagen cross-linking, and loss of water and proteoglycan from the nucleus. Increased levels of cytokines and MMPs probably reflect the initial features of an attempted repair response to injury, as in other connective tissues, and they could be triggered by the abnormal matrix stresses which follow structural disruption (Figure 8). However, because of impaired matrix synthesis, subsequent repair is never achieved. Transport of catabolic mediators within the disc would also be boosted by the presence of gross fissures, thereby propagating matrix damage. Finally, ingrowth of blood vessels and nerves probably represent a late consequence of altered mechanics and biochemistry in severely degenerated discs. Therefore, defining disc degeneration in terms of structural failure leads to a simple conceptual framework, which incorporates most known features of degenerated discs. It also warns that therapeutic attempts to manipulate disc cell physiology may prove futile unless the cells' mechanical environment is also corrected.

This definition is also consistent with the 4 or 5-point scales conventionally used to grade macroscopic disc degeneration.[40,110,111] The first point on these scales refers to young and intact discs, while the final point corresponds to end-stage degeneration, typified by a collapse of disc height (Figure 6D). These scales are exercises in pattern recognition, and although useful, they do not explain or define disc degeneration. Previous definitions of disc degeneration are compatible with the definition proposed here: mechanical damage which … results in a pattern of morphologic and histologic changes;[112] and sluggish adaptation to gravity loading followed by obstructed healing.[80] Epidemiologic studies using MRI necessarily equate disc degeneration with associated structural changes.[1]

An extensive review of nomenclature made clear distinctions between pathologic and age-related changes in discs, and included major structural changes such as radial fissures and disc narrowing in the former category.[113] Referring to tendon degeneration, Riley et al[102] suggests an active, cell-mediated process that may result from a failure to regulate specific MMP activities in response to repeated injury or mechanical strain. There is a growing consensus that degeneration involves aberrant cell-mediated responses to progressively deteriorating circumstances in their surrounding matrix.

Therefore, we propose the following definitions. The process of disc degeneration is an aberrant, cell-mediated response to progressive structural failure. A degenerate disc is one with structural failure combined with accelerated or advanced signs of aging. (The second half of this definition distinguishes a degenerate disc from one that has just been injured, and the reference to aging avoids the practical problem of identifying specific cell-mediated responses to structural failure.) Early degenerative changes should refer to accelerated age-related changes in a structurally intact disc. Degenerative disc disease should be applied to a degenerated disc, which is also painful. This last definition is consistent with the widespread use of the word disease to denote something that can cause distress or dis-ease. Manifestations of structural failure such as radial fissures, disc prolapse, endplate damage, internal or external collapse of the anulus, and disc narrowing can themselves be defined in pragmatic terms as is usual in the epidemiologic and radiologic literature.[65,113,114] Cell-mediated responses to structural failure can be regarded as the final common pathway of the disease process.


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