The intervertebral disc is a cartilaginous structure that resembles articular cartilage in its biochemistry, but morphologically it is clearly different. It shows degenerative and ageing changes earlier than does any other connective tissue in the body. It is believed to be important clinically because there is an association of disc degeneration with back pain. Current treatments are predominantly conservative or, less commonly, surgical; in many cases there is no clear diagnosis and therapy is considered inadequate. New developments, such as genetic and biological approaches, may allow better diagnosis and treatments in the future.

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Degeneration of the intervertebral disc

STUDY DESIGN A histologic study on age-related changes of the human lumbar intervertebral disc was conducted. OBJECTIVES To investigate comprehensively age-related temporospatial histologic changes in human lumbar intervertebral disc, and to develop a practicable and reliable classification system for age-related histologic disc alteration. SUMMARY OF THE BACKGROUND DATA No comprehensive microscopic analysis of age-related disc changes is available. There is no conceptual morphologic framework for classifying age-related disc changes as a reference basis for more sophisticated molecular biologic analyses of the causative factors of disc aging or premature aging (degeneration). METHODS A total of 180 complete sagittal lumbar motion segment slices obtained from 44 deceased individuals (fetal to 88 years of age) were analyzed with regard to 11 histologic variables for the intervertebral disc and endplate, respectively. In addition, 30 surgical specimens (3 regions each) were investigated with regard to five histologic variables. Based on the semiquantitative analyses of 20,250 histologic variable assessments, a classification system was developed and tested in terms of validity, practicability, and reliability. The classification system was applied to cadaveric and surgical disc specimens not included in the development of the classification system, and the scores were assessed by two additional independent raters. RESULTS A semiquantitative analyses provided clear histologic evidence for the detrimental effect of a diminished blood supply on the endplate, resulting in the tissue breakdown beginning in the nucleus pulposus and starting in the second life decade. Significant temporospatial variations in the presence and abundance of histologic disc alterations were observed across levels, regions, macroscopic degeneration grades, and age groups. A practicable classification system for age-related histologic disc alterations was developed, resulting in moderate to excellent reliability (kappa values, 0.49-0.98) depending on the histologic variable. Application of the classification system to cadaveric and surgical specimens demonstrated a significant correlation with age ( < 0.0001) and macroscopic grade of degeneration ( < 0001). However, substantial data scatter caution against reliance on traditional macroscopic disc grading and favor a histology-based classification system as a reference standard. CONCLUSIONS Histologic disc alterations can reliably be graded based on the proposed classification system providing a morphologic framework for more sophisticated molecular biologic analyses of factors leading to age-related disc changes. Diminished blood supply to the intervertebral disc in the first half of the second life decade appears to initiate tissue breakdown.

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

Very little is known about the turnover of extracellular matrix in the human intervertebral disc. We measured concentrations of specific molecules reflecting matrix synthesis and degradation in predetermined regions of 121 human lumbar intervertebral discs and correlated them with ageing and Thompson grade of degeneration. Synthesis in intervertebral discs, measured by immunoassay of the content of a putative aggrecan biosynthesis marker (846) and the content of types I and II procollagen markers, is highest in the neonatal and 2-5-yr age groups. The contents of these epitopes/molecules progressively diminished with increasing age. However, in the oldest age group (60-80 yr) and in highly degenerated discs, the type I procollagen epitope level increased significantly. The percentage of denatured type II collagen, assessed by the presence of an epitope that is exposed with cleavage of type II collagen, increased twofold from the neonatal discs to the young 2-5-yr age group. Thereafter, the percentage progressively decreased with increasing age; however, it increased significantly in the oldest group and in highly degenerate discs. We identified three matrix turnover phases. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of type II collagen. Phase II (maturation and ageing) is distinguished by a progressive drop in synthetic activity and a progressive reduction in denaturation of type 11 collagen. Phase III (degeneration and fibrotic) is illustrated by evidence for a lack of increased synthesis of aggrecan and type II procollagen, but also by an increase in collagen type II denaturation and type I procollagen synthesis, both dependent on age and grade of tissue degeneration.

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The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.

Study design A review of the literature on disc nutrition. Objectives To summarize the information on disc nutrition in relation to disc degeneration. Summary of the background data The disc is avascular, and the disc cells depend on diffusion from blood vessels at the disc's margins to supply the nutrients essential for cellular activity and viability and to remove metabolic wastes such as lactic acid. The nutrient supply can fail due to changes in blood supply, sclerosis of the subchondral bone or endplate calcification, all of which can block transport from blood supply to the disc or due to changes in cellular demand. Methods A review of the studies on disc blood supply, solute transport, studies of solute transport in animal and human disc in vitro, and of theoretical modeling studies that have examined factors affecting disc nutrition. Results Small nutrients such as oxygen and glucose are supplied to the disc's cells virtually entirely by diffusion; convective transport, arising from load-induced fluid movement in and out of the disc, has virtually no direct influence on transport of these nutrients. Consequently, there are steep concentration gradients of oxygen, glucose, and lactic acid across the disc; oxygen and glucose concentrations are lowest in the center of the nucleus where lactic acid concentrations are greatest. The actual levels of concentration depend on the balance between diffusive transport and cellular demand and can fall to critical levels if the endplate calcifies or nutritional demand increases. Conclusions Loss of nutrient supply can lead to cell death, loss of matrix production, and increase in matrix degradation and hence to disc degeneration.

Nutrition of the intervertebral disc.

This review article describes anatomy, physiology, pathophysiology and treatment of intervertebral disc. The intervertebral discs lie between the vertebral bodies, linking them together. The components of the disc are nucleus pulposus, annulus fibrosus and cartilagenous end-plates. The blood supply to the disc is only to the cartilagenous end-plates. The nerve supply is basically through the sinovertebral nerve. Biochemically, the important constituents of the disc are collagen fibers, elastin fibers and aggrecan. As the disc ages, degeneration occurs, osmotic pressure is lost in the nucleus, dehydration occurs, and the disc loses its height. During these changes, nociceptive nuclear material tracks and leaks through the outer rim of the annulus. This is the main source of discogenic pain. While this is occurring, the degenerative disc, having lost its height, effects the structures close by, such as ligamentum flavum, facet joints, and the shape of the neural foramina. This is the main cause of spinal stenosis and radicular pain due to the disc degeneration in the aged populations. Diagnosis is done by a strict protocol and treatment options are described in this review. The rationale for new therapies are to substitute the biochemical constituents, or augment nucleus pulposus or regenerate cartilaginous end-plate or finally artificial disc implantation..

Intervertebral disc: anatomy-physiology-pathophysiology-treatment.

The metabolism of the canine nucleus pulposus was investigated at different oxygen tensions. It was found that even at high oxygen tensions the metabolism is mainly anaerobic, only approximately 1.5% of the glucose being converted to carbon dioxide. The concentration dependence of oxygen consumption is limited to very low oxygen tensions. Values of oxygen consumption and lactic acid production were used to calculate the concentration profiles of these substances within the nucleus pulposus, using a diffusion theory. The predicted concentration profiles were compared with the experimental measurements of concentration at various positions in the disc. The good agreement in these values found in the nucleus confirms that the main mechanism of metabolite transport is diffusion, and the main route of nutrient supply into the nucleus is via the endplate.

Nutrition of the intervertebral disc: solute transport and metabolism.

Adult dogs were injected intravenously with /sup 35/S-sulphate, and moderately exercised for one to six hours to measure isotope concentrations and profiles throughout the intervertebral discs. The isotope profiles were also observed in control animals that had been under anesthesia between injections and death. In both sets of animals, the profiles were in agreement with those expected for isotope transport by diffusion. This agreement indicates that fluid pumping during movement has an insignificant effect on transport of nutrients into the disc. Small solutes, e.g., O/sub 2/, glucose, and sulphate, are transported into the disc chiefly by diffusion. However, calculations show that because of their low diffusivities, pumping may increase the rate of transport of large solutes into the disc, as it does in articular cartilage.

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

The main mechanism for solute transport within the intervertebral disk is passive diffusion. The 2 routes for the exchange of solutes with the blood vessels outside the disk are via the periphery of the annulus, and through the end-plates. While the periphery of the annulus is completely permeable, the bone--disk interface is only partially so. In the region of the nucleus the effective area through which solute transport is taking place constitutes some 85% of the actual bone/disk interface; in the region of the inner annulus it is reduced to only 35% while the bone--disk interface at the outer annulus is almost completely impermeable. These figures, calculated from tracer diffusion experiments correlate very well with the qualitative observations of blood vessel contact. Apart from its dependence on the permeability of the endplate, solute diffusion is also determined by the nature of the solute. For example, a negatively charged solute such as the sulphate ion is considerably excluded from the nucleus, which limits its rate of penetration via the endplates. The sulphate uptake by the disk cells to produce glycosaminoglycans is low and comparable to that in articular cartilage.

S. Holm

Papers

Nutrition of the intervertebral disc: solute transport and metabolism.

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

Nutrition of the intervertebral disk. An in vivo study of solute transport.

Diffusion of small solutes into the intervertebral disc: as in vivo study.