Annulus Fibrosus

The annulus fibrosus is the outer circumferential portion of the disc and is often subdivided into the inner and outer annulus. The outer annulus is a collection of highly organized, densely packed collagen fibrils, creating a lamellar structure of up to 25 lamellae in the mature disc. These collagen fibrils insert into the adjacent vertebral end plates and join them together to stabilize the spine. In addition to its predominantly collagenous structure, a small amount of elastin is present in the annulus, which helps it to restore and recoil after stretching in response to compression and tensile forces. The strong annulus provides the ability to absorb significant hoop stresses and maintain stiffness in the presence of the tensile forces induced by bending and twisting of the spine. The importance of this ability to resist hoop stress has been shown in large animal studies, which demonstrated that even a partial-thickness laceration into the annulus rapidly produced advanced disc degeneration. The outer annulus is populated with a low density of fibroblast-like cells. It is the only tissue in the mature disc that remains innervated and is capable of producing pain when exposed to noxious stimuli.

The inner annulus appears to serve as a transition zone to the vastly different biochemical composition of the nucleus. It is less dense and lacks the organized lamellar structure of the outer annulus. It is populated with rounder, chondrocyte-like cells, and the concentration of proteoglycans and water content is increased.

Nucleus Pulposus

The nucleus pulposus, which is the inner, less-organized region of the disc, occupies the middle and posterior thirds of the intervertebral disc. It consists of a rich proteoglycan matrix with a lesser amount of disorganized collagen than in the anulus. There is a significantly higher content of water in the nucleus. The large amounts of proteoglycan and water present in the nucleus make it ideal for developing the “swelling pressures” necessary to resist the compressive forces of the spine. At birth, the nucleus is populated almost exclusively with notochordal cells. These cells rapidly begin to necrose shortly after birth and by the age of 4 to 10 years they are completely replaced by rounder, chondrocyte-like cells of mesenchymal origin ( Table 16-1 ).

Cartilaginous End Plate

The cartilaginous end plate is a hyaline cartilage layer separating the disc from the adjacent bony vertebral end plate. It is usually less than 1 mm thick in the mature disc and lies immediately adjacent to the perforated bony end plate. It is loosely cemented to the underlying bony end plate by a thin layer of calcium that is absent near the perforated areas of the bony plate, which allows for nutrient diffusion from the vertebra to the disc.

Anabolic Influences

The intervertebral disc matrix is in a constant state of dynamic flux. Anabolic and catabolic influences on the disc matrix continuously interact with the disc to alter the physical composition of the matrix. Metalloproteinases (MMPs) modulate the matrix composition by breaking down aged proteoglycans under catabolic influences while newly synthesized matrix takes the place of the degraded proteoglycans. A complex, multifactorial, poorly understood interaction of mechanical and biochemical factors defines whether a disc is capable of remodeling in response to loading conditions in order to maintain disc homeostasis. If the disc is unable to remodel and maintain a balance of anabolic and catabolic influences, then damage accumulates in a process that may eventually self-perpetuate into a state of continued degeneration.

The key anabolic modulating growth factors work by stimulating the chondrocyte-like cells to produce matrix while inhibiting the MMPs present in the disc. In addition to various growth factors, tissue inhibitors of MMPs (TIMPs) are present to suppress the activation of the MMPs ( Table 16-2 ).

Catabolic Influences

Catabolic modulation in the disc occurs mainly through cytokine-induced and metalloproteinase degradation of matrix components. MMPs 1, 2, 3, 8, 9, and 13 are all present in the disc and serve to degrade collagen, aggrecan, versican, link protein, and the other proteoglycans. The aggrecanases ADAM-TS-4 and ADAM-TS-5, from the ADAM ( a d isintegrin a nd m etalloproteinase) protein family, are also present in the disc and mainly function to degrade aggrecan and versican. These MMPs and aggrecanases allow for the large proteoglycans to be degraded into smaller components that may be more easily reached from the intervertebral disc by diffusion. In a pathologic catabolic state when the MMPs are working with little opposing matrix production, a significant net loss of proteoglycan and water content occurs, rendering the disc incapable of producing the swelling pressure necessary to resist compressive forces on the disc. Overproduction of MMPs can thus lead to increased forces on other spinal structures and contribute to disc and overall spinal degeneration.

In addition to the catabolic effect of MMPs, growing evidence suggests that inflammatory cytokines may have a significant catabolic influence on the disc. Animal studies have indicated that in the presence of injury to the intervertebral disc there are increased levels of interleukin (IL)-1, tumor necrosis factor alpha (TNF-α), and IL-8 near the injured regions of the disc. These cytokines have negative catabolic effects on the disc and also stimulate the disc cells to produce chemokines, which are responsible for macrophage attraction and stimulation, especially in the presence of disc herniation. Macrophages in the disc usually reflect an attempt to break up or remove herniated disc fragments, but their presence also leads to further inflammation and cytokine release, which may prove damaging to the disc. These inflammatory substances are also responsible for the activation of multiple cascades within the disc cell nuclei that lead to the production of metalloproteinases, which in turn contribute to matrix breakdown. In addition, these inflammatory cytokines are thought to contribute to the pain-producing effects of disc degeneration ( Table 16-3 ).

Gross and Histologic Changes

The hallmark histologic finding in intervertebral disc degeneration is the progressively diminishing vascular supply, which begins shortly after birth and leads to tissue breakdown as early as the second decade of life. Changes in the nucleus pulposus also begin immediately after birth. Within the first two decades of life, the nucleus begins to undergo mucoid degeneration, increasing cleft formation, and granular changes consistent with granulation tissue formation at sites of disc injury. These clefts and granular changes eventually lead to frank tears that communicate with annular rim lesions.

In the annulus, peripheral rim lesions appear late in the second decade of life and eventually progress to frank tears that communicate with the nuclear clefts. The end plate also shows degenerative changes that begin with the loss of the end plate vessels early in childhood. After the loss of these vessels, cartilage disorganization increases and cracks in the cartilaginous end plate begin to appear. Microfractures in the adjacent subchondral bone follow, and new subchondral bone formation and eventual sclerosis of the plate occur. All of these changes eventually lead to a “burned-out” state, apparent in the seventh and later decades of life. At this time, all components of the disc begin to resemble scar tissue and there is no longer a distinction among the different regions of the disc ( Table 16-4 and Figs. 16-3 to 16-6 ).

Sagittal section through a normal intervertebral disc.

(From Thalgott J, Albert T, Vaccaro A, et al: A new classification system for degenerative disc disease of the lumbar spine based on magnetic resonance imaging, provocative discography, plain radiographs and anatomic considerations. Spine J 2004;4[6 Suppl]:167S.)

Sagittal section through a disc with mild degeneration.

(From Thalgott J, Albert T, Vaccaro A, et al: A new classification system for degenerative disc disease of the lumbar spine based on magnetic resonance imaging, provocative discography, plain radiographs and anatomic considerations. Spine J 2004;4[6 Suppl]:167S.)

Sagittal section through a disc with moderate degeneration. Note loss of disc height and irregular end plates.

(From Thalgott J, Albert T, Vaccaro A, et al: A new classification system for degenerative disc disease of the lumbar spine based on magnetic resonance imaging, provocative discography, plain radiographs and anatomic considerations. Spine J 2004;4[6 Suppl]:167S.)

Sagittal section through a disc with severe degeneration. Note end plate sclerosis, osteophytosis, and severe loss of disc height.

(From Thalgott J, Albert T, Vaccaro A, et al: A new classification system for degenerative disc disease of the lumbar spine based on magnetic resonance imaging, provocative discography, plain radiographs and anatomic considerations. Spine J 2004;4[6 Suppl]:167S.)

The cellular content of the disc also changes over time. The earliest changes occur shortly after birth and include replacement of the rapidly decaying notochordal cells with mesenchymal chondrocyte-like cells. Cell density in both the nucleus and the annulus also rapidly declines after birth. This occurs as the matrix grows along with the expanding volume of the intervertebral disc. The cell density in the nucleus pulposus shortly after birth is approximately 4 × 10 ⁶ cells/cm ³ , and in the annulus fibrosus it is 9 × 10 ⁶ cells/cm ³ . This is significantly lower than the cellular density of even relatively acellular hyaline cartilage, which has about 1.4 × 10 ⁷ cells/cm ³ . As the disc continues to age, cell death accelerates and large numbers of decaying cells can be found in clusters. By adulthood, more than 50% of the disc’s cells are necrotic ( Fig. 16-7 and Table 16-5 ).

Midsagittal view on T2 density-weighted MRI of discs graded according to a modified Pfirrmann classification (see Table 16-5 ).

(From Hangai M, Kaneoka K, Kuno S, et al: Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J 2008;8:732.)

Radiographic Changes

Several patterns of radiographic changes have been associated with intervertebral disc degeneration. Disc space collapse and osteophyte formation at the end plates are often apparent on plain radiographs. Changes observed on magnetic resonance imaging (MRI) include loss of disc height, decrease in disc water content (visualized by diminished signal in the disc on T2-weighted sequences), and the presence of annular tears. Modic changes to the vertebral body end plates constitute several different types of signal abnormalities on MRI, and are summarized in Table 16-6 . The inter- and intraobserver reliability for assessing these segmental changes on MRI is high. However, it is important to note that the presence or absence of these radiographic changes does not necessarily contribute to a patient’s symptomatology, and degenerative changes are often present in asymptomatic individuals.

Biochemical Changes

The most significant biochemical change in the degenerating disc is the net loss of proteoglycan. In addition to this quantitative loss of proteoglycan, the quality of the remaining proteoglycan is compromised. With the loss of large quantities of aggregated proteoglycan, the disc’s ability to create the swelling pressure necessary to absorb the forces imposed on it decreases. These changes also begin shortly after birth, when the rich proteoglycan matrix composition is altered. At birth, chondroitin sulfate is the predominant glycosaminoglycan in the disc, but as the blood supply is progressively lost and the disc volume increases, the disc contents become increasingly anaerobic. Because of the lack of oxygen, chondroitin sulfate is progressively replaced by keratan sulfate chains, which are created in the absence of oxygen.

In addition to the changing glycosaminoglycan composition in the disc, the overall structure of the large proteoglycans changes. In the young disc, aggrecan is the predominant proteoglycan. Multiple aggrecan molecules bind to hyaluronan to form an even larger structure called an aggregate . In the fetal and newborn disc, aggregating proteoglycans predominate and are extremely effective in creating large swelling pressures. The amount of aggregating proteoglycan is rapidly diminished with age by proteolytic degradation of the large aggregates. By 6 months of age, only 50% of the annular and 30% of the nuclear proteoglycan content is in aggregated form. In the mature adult disc, only 10% of the proteoglycan is aggregated and these aggregates are smaller and have a higher keratan sulfate composition compared with their younger equivalents. These degenerative features of disc proteoglycans may make them less effective in creating the swelling pressure necessary to resist compressive forces ( Fig. 16-8 ). Progressive nucleus pulposus dehydration subsequently follows, ultimately leading to disc desiccation and loss of homeostatic and mechanical properties of the disc.

The large aggrecan molecule forms an aggregate with hyaluronan and link protein.

(Redrawn, with permission of Springer Science and Business Media, from Rodén L. Structure and Metabolism of Connective Tissue Proteoglycans. In Lennarz WJ, editor: The biochemistry of glycoproteins and proteoglycans, New York: Plenum Press; 1980:291, 267-371.)

The collagen content of the disc is not immune to change, also exhibiting signs of degeneration. The disc collagen demonstrates evidence of proteolytic collagenase action, which accumulates and eventually contributes to the weakening mechanical properties of the disc. It is significant that the triple helix structure of disc collagen is more denatured and damaged than that of the collagen in articular cartilage, which may indicate less effective repair mechanisms in the disc. In addition, the collagen present in the disc appears to be nonenzymatically cross-linked by advanced glycation end products (AGEs).

AGEs are protein modifiers formed through the Maillard reaction when an amino acid and a reducing sugar react. With age, AGEs accumulate in various tissues in the body such as the skin, myocardial cells, renal cells, chondrocytes, and intervertebral discs. AGEs originally were given substantial attention because of their increased presence in diabetes. After research elucidated the presence and negative effect of AGEs on articular cartilage, their presence and potential role in intervertebral disc degeneration were sought. In vitro and animal studies suggest that AGEs play a role in disc degeneration. Their increased concentration in diabetes may contribute to the increased relative risk for disc herniation seen in at least one study of patients with diabetes.

AGEs likely influence disc degeneration through negative biologic and biomechanical contributions. Biomechanical studies have demonstrated that the accumulation of AGEs leads to alterations in the disc’s physical properties, the most significant of which is increased mechanical stiffness. This increased stiffness of the disc also likely leads to a decreased ability to produce the swelling pressure necessary for normal disc function. Biologic in vitro studies have also demonstrated that the accumulation of AGEs in intervertebral disc cells leads to a down-regulation in the production of aggrecan. In addition, a bovine study documented the increased expression of the receptor for AGEs (RAGE) in intervertebral discs in the presence of an inflammatory state with increased IL-1β. All of these studies noted a decrease in aggrecan production, which may at least partially explain the increased disc degeneration seen in the presence of chronic inflammation.

Associated with this progressive loss of vascular supply and decrease in proteoglycan content is dysregulation of cell reparative mechanisms. Oxidative stress, secondary to higher numbers of oxidized proteins and the inability of the disc to clear these proteins, is partially responsible for the increased rate of apoptosis of notochordal remnant cells. Proliferation of chondrocyte-like cells is also observed simultaneously, which alters normal intradiscal homeostasis and results in an overall increase in cell density; however, the majority of the cells localized to the disc are dead, which contributes to the alteration in global biomechanical properties of the disc.

Disc Material Properties and Disc Degeneration

The gross structural and biochemical changes associated with early degeneration lead to changes in the intervertebral disc’s mechanical properties, which make it less capable of performing its necessary functions. Cadaveric studies conducted on discs of various ages and degrees of degeneration have demonstrated an increased shear modulus in aged and degenerated discs, indicating a decreased ability of the disc to absorb energy. In essence, the discs become increasingly stiff and appear to undergo a transition from “fluid-like” behavior to “solid-like” behavior with increasing degeneration. This transition is relevant in that it is significantly correlated with alterations in the biomechanics of the entire motion segment. Many studies have evaluated alterations in degenerated motion segments without a clear consensus on the role of segmental instability in the diagnosis and treatment of disc degeneration. Alterations in disc viscoelasticity have also been seen, including both increased creep and creep rate. In addition to these changes, which more drastically affect the nucleus, alterations in the annulus result in a decreased Poisson ratio as well as decreased radial permeability, which transforms the anisotropic hydraulic permeability of the normal disc to a more isotropic permeability in degenerated discs ( Box 16-1 ).

With the compromised material properties demonstrated in degenerative models, abnormal motion segments are to be expected and have been demonstrated in cadaveric models. These studies suggest that early human disc degeneration and the changing physical properties of the disc may affect the overall mechanical function of the spine, leading to altered dynamics and increased intradiscal pressure as well as increased internal stress and strain patterns on the disc, which ultimately may contribute to further disc degeneration.