The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 88, Issue suppl 2

Workshop Articles | April 01, 2006

Histology and Pathology of the Human Intervertebral Disc

Sally Roberts, PhD; Helena Evans, BSc; Jayesh Trivedi, MCh(Orth), FRCS, FRCS(Tr&Orth); Janis Menage, HND

Note: The authors are grateful to Mrs. Lynn Murphy for support.

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the European Union research project EURODISC QLK6-CT-2002-02582. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2006 Apr 01;88(suppl 2):10-14. doi: 10.2106/JBJS.F.00019

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Abstract

The intervertebral disc is a highly organized matrix laid down by relatively few cells in a specific manner. The central gelatinous nucleus pulposus is contained within the more collagenous anulus fibrosus laterally and the cartilage end plates inferiorly and superiorly. The anulus consists of concentric rings or lamellae, with fibers in the outer lamellae continuing into the longitudinal ligaments and vertebral bodies. This arrangement allows the discs to facilitate movement and flexibility within what would be an otherwise rigid spine. At birth, the human disc has some vascular supply within both the cartilage end plates and the anulus fibrosus, but these vessels soon recede, leaving the disc with little direct blood supply in the healthy adult. With increasing age, water is lost from the matrix, and the proteoglycan content also changes and diminishes. The disc—particularly the nucleus—becomes less gelatinous and more fibrous, and cracks and fissures eventually form. More blood vessels begin to grow into the disc from the outer areas of the anulus. There is an increase in cell proliferation and formation of cell clusters as well as an increase in cell death. The cartilage end plate undergoes thinning, altered cell density, formation of fissures, and sclerosis of the subchondral bone. These changes are similar to those seen in degenerative disc disease, causing discussion as to whether aging and degeneration are separate processes or the same process occurring over a different timescale. Additional disorders involving the intervertebral disc can demonstrate other changes in morphology. Discs from patients with spinal deformities such as scoliosis have ectopic calcification in the cartilage end plate and sometimes in the disc itself. Cells in these discs and cells from patients with spondylolisthesis have been found to have very long cell processes. Cells in herniated discs appear to have a higher degree of cellular senescence than cells in nonherniated discs and produce a greater abundance of matrix metalloproteinases. The role that abnormalities play in the etiopathogenesis of different disorders is not always clear. Disorders may be caused by a genetic predisposition or a tissue response to an insult or altered mechanical environment. Whatever the initial cause, a change in the morphology of the tissue is likely to alter the physiologic and mechanical functioning of the tissue.

Figures in this Article

The Normal Intervertebral Disc

The intervertebral discs are cartilaginous, articulating structures between the vertebral bodies that allow movement (flexion, extension, and rotation) in the otherwise rigid anterior portion of the vertebral column. The discs form a very complex system, with an outer anulus fibrosus surrounding a central nucleus pulposus. Collagen fibers continue from the anulus into the adjacent tissues, tying this fibrocartilaginous structure to the vertebral bodies at its rim, to the longitudinal ligaments anteriorly and posteriorly, and to the hyaline cartilage end plates superiorly and inferiorly. The cartilage end plates in turn lock into the osseous vertebral end plates via the calcified cartilage, with few, if any, collagen fibers crossing the boundary.

Development of the Intervertebral Disc

Most of the spinal column, the vertebrae, the cartilage end plates, and the anulus fibrosus develop from mesoderm. The embryonic nucleus pulposus, in contrast, derives from endoderm, being a remnant of the notochord. The vertebral column develops in the human embryonic mesoderm at approximately four weeks' gestation, requiring both the central notochord and neural tube for its induction. The centrum of each vertebra forms from the fusion of the lower and the upper region of adjacent somites, with the intersegmental artery running horizontally between them. The developing vertebral body surrounds the notochord, which expands very dramatically and extensively at a well-defined time point (e.g., the sixteenth day of gestation [E16] in the rat embryo). The cells in the outer region of what will become the intervertebral disc align into sheets, adjacent layers of which are oriented at alternate directions to the vertebral axis¹. They then synthesize collagen fibers in the same planes, leading to the highly organized lamellar structure typical of the normal anulus fibrosus (Fig. 1, A). The origin of the adult nucleus pulposus is less well understood; some authors attribute it to the notochord, while others believe the notochord rescinds and the nucleus is formed starting from the inner aspect of the anulus and moving inward. The mechanism likely differs between species. In some animals, notochordal cells remain to adulthood (Fig. 2, D); in humans, however, the number of notochordal cells in the nucleus pulposus diminishes rapidly after birth, with 2000 cells per mm² at six weeks of age but only 100 cells per mm² at one year, and none identifiable after the age of four years².

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Fig. 1: Histologic findings. A: Specimen from a 2.5-year-old human shows how regular concentric lamellae can be seen when the specimen is viewed with polarized light. B: Specimen from a human neonate, showing how the outer aspect of the anulus fibrosus and the cartilage end plate are vascularized with blood vessels (arrows) and vascular channels (asterisks). (Figs. 1, A and 1, B stained with hematoxylin and eosin; original magnification, ×10 and ×30, respectively.) C: Herniated disc specimen from a seventy-four-year-old woman, showing how large numbers of blood vessels can reappear with degeneration, whereas in normal discs, these structures recede with age (specimen stained with the endothelial marker, QBEnd/10; original magnification, ×250). OAF = outer aspect of the anulus fibrosus; CEP = cartilage end plate.

At birth, the human cartilage end plates make up approximately 50% of the intervertebral space (compared with approximately 5% in the adult) and have large vascular channels running through them. The intervertebral disc of the young human also has some blood vessels running between the lamellae of the anulus fibrosus (Fig. 1, B), where nerves are commonly found. Soon after birth, the vascular channels of the cartilage end plate fill in with extracellular matrix such that no channels remain by the first decade of life, with a similar reduction in the vessels in the anulus. Thus, the intervertebral disc in adulthood is often described as the largest avascular tissue in the body and certainly renders cells of the disc, particularly in the central nucleus, a long way from a source of nutrients or clearance of metabolites.

The cartilage end plate in humans functions in early life as a growth plate for the adjacent vertebral body; its structure is typical of that seen in the epiphyseal growth plate of long bones. This structure is lost during skeletal maturity, so that, by adulthood, the cartilage end plate is a layer of hyaline cartilage (approximately 0.6 mm thick) with calcified cartilage adjoining the bone³. It occupies the central 90% of the interface between the disc and the vertebral body, encompassed by a ring of bone that forms via the epiphysis fusing with the vertebral body in this rim region.

The Normal Adult Intervertebral Disc

The normal human intervertebral disc in adulthood consists of a large amount of extracellular matrix interspersed by a small number of cells that make up approximately 1% of the total volume. The cells are believed to be made up of at least two phenotypically distinct populations⁴.

The cells are morphologically different; those in the anulus fibrosus and cartilage end plate are more elongated and fibroblast-like (Fig. 2, A) compared with those of the nucleus pulposus, which are more rounded or oval and chondrocyte-like, sometimes with a capsule around them (Fig. 2, B). These apparent simplistic shapes belie the complexity that may be present, with cells often having extensive, long, thin cell processes that are possibly involved in sensing mechanical strain (Fig. 2, C)⁵. In addition, these two populations behave differently, such as in their response to applied loads or in synthesizing different matrix molecules when grown in culture. Nucleus pulposus cells generally synthesize only type-II collagen in alginate beads, whereas anulus fibrosus cells produce both type-I and type-II collagen⁴. This reflects the extracellular matrix molecules found in the nucleus and anulus of the disc in vivo.

Macroscopically, the healthy adult intervertebral disc is seen to consist of the two regions, the central nucleus pulposus and the outer anulus fibrosus, with its concentric lamellae. When sections of the disc are viewed under polarized light, the orientation of the collagen bundles is demonstrated very clearly. Discs from the human lumbar spine have been shown to have fifteen to twenty-five lamellae in the anulus⁶. These lamellae begin life as individual discrete bundles of collagen fibers. In humans, however, lamellar organization becomes increasingly complex with more bifurcation and interdigitations as the individual ages, and the lamellae increase in thickness⁶.

Biochemical analysis of discs has identified the molecular components and provides gross quantitative information on the amounts present. However, a huge variation exists in the distribution of many of these components with regard to location in the disc, the extent of which only becomes apparent with histochemical, immunohistochemical, or electron microscopic techniques. Elastin, for example, constitutes only 2% of the dry weight of the anulus, suggesting that it is not a major component. It may, however, contribute greatly to the functioning of the disc because it has a very discrete and specific localization in the normal disc, mainly between the lamellae, with a few fibers crossing perpendicularly⁷. Various glycosaminoglycans and types of collagen have been demonstrated to be preferentially localized in certain places. For example, type-III and type-VI collagen (also making up a small proportion biochemically) are found predominantly pericellularly; this is likely to be a reflection of their function within the disc. Nerves and blood vessels are both present to a limited degree in the healthy adult disc, restricted to the outer few millimeters of the anulus fibrosus. A small number of mechanoreceptors are also present, most commonly having the morphology of Golgi tendon organs, a few Ruffini receptors, and even fewer pacinian corpuscles⁸.

Changes with Age

Major age-related changes in the cartilage end plate and intervertebral disc in humans are reported to occur at the end of the first decade of life⁹. Even before this, as early as two years of age, mild microscopic degenerative changes are seen, including decay and/or proliferation of nucleus pulposus cells, mild cleft formation, alterations in cell density, and matrix degeneration in the cartilage end plate⁹. This coincides with, and may be the result of, regression of blood vessels in the anulus, cartilage, and osseous end plates. A study of cadaveric human vertebrae demonstrated that the number of vascular channels perforating the osseous vertebral end plate diminishes drastically between six and thirty months of age¹⁰. It has been observed that the disc undergoes degenerative changes earlier in life than other tissues do^11,12; it is likely that the rapid reduction in nutrient supply contributes to this early degeneration.

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Fig. 2: Histologic findings. A and B: Specimen from a thirty-five-year-old adult, showing that cell morphology varies, depending on location within the disc as well as age and pathology. A: Cells of the anulus fibrosus and cartilage end plate are much more bipolar and elongated. B: In contrast, the nucleus pulposus cells (thin arrow) are rounded, often sitting inside a capsule (thick arrow) that may be surrounded by an obvious pericellular matrix (arrowhead). (Specimens in Figs. 2, A and 2, B stained with hematoxylin and eosin; original magnification, approximately, ×400.) C: Disc specimen from a fourteen-year-old patient with spondylolisthesis, showing how cell processes that can be visualized by staining (e.g., for vimentin) are often long and numerous, particularly in disc specimens from patients with scoliosis and spondylolisthesis. (Reprinted, with permission of Blackwell Publishing, from: Johnson WE, Roberts S. Human intervertebral disc cell morphology and cytoskeletal composition: a preliminary study of regional variations in health and disease. J Anat. 2003;203:605-12.) D: Specimen from a newborn human, showing how notochordal cells are present in the nucleus pulposus at birth in humans (hematoxylin and eosin stain; original magnification, approximately ×400). E: Specimen from a thirty-seven-year-old woman, showing how cell clusters are seen in disc degeneration (hematoxylin and eosin stain; original magnification, approximately ×400). F and G: Cells within clusters can produce matrix metalloproteinases (MMPs). (F) Degenerative disc specimen from a fifty-nine-year-old woman, showing staining for MMP1 and molecules seen only in the presence of inflammation, for example (G), TSG-6, as shown in this specimen from a forty-four-year-old woman. H: Specimen from a fifty-four-year-old patient, showing that cells within clusters also demonstrate a greater degree of cell senescence than single cells (specimen stained with the marker of senescence, SA-ß-galactosidase).

Boos et al.⁹ described in detail the progressive changes in disc histology that occur with age. These changes include an increased number and extent of clefts and tears, the presence of granular material, and neovascularization from the outer aspect of the anulus inwards. Cell proliferation, cluster formation¹³, and a greater level of cell death also occur. Loss of demarcation between the anulus and the nucleus also increasingly occurs with age, from the second decade onward. More structural dis-organization of the cartilage end plate, including cracks, thinning of the end plate, altered cell density, microfracture in the adjacent subchondral bone, and bone sclerosis, is also found with increasing age. These changes in the end plate precede changes in the nucleus pulposus, with alterations in the anulus fibrosus (particularly the outer region) occurring later in life.

Changes with Disc Degeneration

Degenerative Disc Disease

Disc degeneration is typified histologically by changes at the cellular level. For example, increased disc-cell proliferation and cell-cluster formation occur (Fig. 2, E), as well as increased cell death (possibly by both apoptosis and necrosis)^13-15. Molecular changes are also seen, such as increased production of cytokines and matrix-degrading enzymes (e.g., matrix metalloproteinases [MMPs]) (Fig. 2, F). Different types of structural matrix molecules can be produced, such as collagen type-I, III, VI, and X, elastin, fibronectin, and amyloid, or their distribution can be altered^7,16-19. Glycosaminoglycans are reduced in disc degeneration (and also with aging) such that staining with any metachromatic stain (e.g., toluidine or alcian blue) is diminished.

Gross matrix changes, including increased lamellar dis-organization and fissures, are features of degenerative discs, together with an increased degree of vascularization and innervation (Fig. 1, C)^20,21. Because these changes are similar to those occurring with increasing age, researchers are faced with the difficulty of differentiating degeneration of the intervertebral disc that occurs purely as an aging phenomenon and degeneration that occurs as part of a pathologic process^9,11. Schmorl nodes (vertebral end-plate lesions, occurring in 76% of individuals) are likewise controversial as to whether they are related to age or degeneration. This may depend on their location in the spine; those in the thoracolumbar region (T10-L1) are reported to be unrelated to age but related to disc degeneration, whereas this appears not to be the case in the lower lumbar discs (L2-L5)²². Beadle¹¹ suggests that "morbid changes" are simply the early appearance of aging processes brought on by unduly severe functional strain. Considerable support is offered for this suggestion, with no real microscopic morphologic features that can be identified as unique to degeneration and not aging or vice versa. In contrast, Twomey and Taylor²³ suggested that a reduction in disc height might be a pathologic feature but not a normal aging process.

Herniated Intervertebral Disc

The histology of herniated discs is quite variable, as is the degree of structural damage, ranging from protrusions (when the outer anular lamellae remain intact) to extrusions (when they are ruptured) to sequestrations (in which the herniation is completely detached from the body of the disc). The morphology of all of these herniations can be very heterogeneous and may include tissue that appears to be from the nucleus pulposus, anulus fibrosus, or cartilage end plate. In an unpublished study conducted in our laboratory, we found that 34% of samples had the morphology of anulus; 34%, nucleus; and 32%, both²⁴. In addition, 20% of samples contained portions of the cartilage end plate. Herniated discs are often much more vascularized (52% of samples in the study just noted) than normal intervertebral discs are. Herniated discs also have a higher frequency of immunopositivity for MMPs, particularly MMP8 and MMP7 (four and two times greater than autopsy discs, respectively)¹⁶. Although cells of most human discs appear to be able to produce cytokines and inflammatory mediators (e.g., interleukins, tumor necrosis factor [TNF]-a, monocyte chemoattractant protein-1, and TNF-a stimulating gene [TSG-6]), they are more commonly found in herniated discs compared with normal discs (Fig. 2, G)²⁵. These samples are also more highly innervated than normal discs, with 80% having nerves present²⁴. A greater proportion of the cells of herniated discs have been shown to be more senescent than those of nonherniated discs—8.5% in herniated discs versus 0.85% in nonherniated discs (Fig. 2, H)²⁶.

Spinal Deformities

Intervertebral discs from patients with spinal deformities such as kyphosis or scoliosis can show morphologic differences from unaffected individuals. One striking feature of scoliosis is the ectopic calcification of the cartilage end plate, which occurs in varying degrees. This begins at the bipolar edges of the cells and spreads to encompass the whole cell and beyond²⁷. The calcification interferes with the flow of nutrients and metabolites through the end plate to and from the disc²⁸. This may be part of the reason for the low number of viable cells in scoliotic discs²⁹. Major changes take place in collagen turnover in different localities within the scoliotic discs, with a shift in the type of collagens being produced; more type-I and minor collagens (such as types III, VI, IX, and X) are present than usual. Gross remodeling of collagen bundles of anular lamellae also occurs. The elastic fiber network, which is so organized between the lamellae in the normal disc, is very sparse and quite disorganized in the scoliotic disc⁷. Cells in deformed discs, such as discs with scoliosis or spondylolisthesis, are characterized by long and often multiple cell processes (Fig. 2, C)³⁰, possibly reflecting the abnormal loads to which this tissue is subjected.

Summary

Histology of the intervertebral disc clearly demonstrates that it is a highly specialized and organized tissue that is normally well integrated with its adjacent tissues. However, it is continually changing as a result of development, aging, and diseases. The alterations that occur undoubtedly affect the mechanical and physiologic functioning of the tissues and may well play a role in the pathogenesis of these disorders. Calcification of the end plate, for example, will diminish solute transport through it, altering the ionic composition around the disc cells, which in turn will affect the metabolism and functioning of the disc. This in turn is likely to lead to decreased or altered cell metabolism, which may include decreased synthesis of extracellular matrix molecules, increased degradative enzymes, or a change in the cell cycle or viability of the disc.

Environmental factors can precipitate the death of the cells through either apoptosis or necrosis; these cellular processes can in turn contribute further to the pathogenesis of the disc disorder. Identifying which of these pathways leads to the most potent degradation and at what stage the pathways can be interrupted or even reversed is important so that therapies can then be targeted at these processes. ?

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Topics

herniated disc ; bone plates ; cartilage ; intervertebral disc ; histology ; nucleus pulposus ; annulus fibrosus ; spinal deformities ; degenerative disc disease

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Sally Roberts, Helena Evans, Jayesh Trivedi, Janis Menage; Histology and Pathology of the Human Intervertebral Disc. The Journal of Bone & Joint Surgery. 2006 Apr;88(suppl_2):10-14.

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