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Journal of Back and Musculoskeletal Rehabilitation Journal of Back and Musculoskeletal Rehabilitation 9 (1997) 23-27
Back to the future: what have we learned from 25 years of research into intervertebral disc biology? Jill Urban* Physiology Laboratory, Oxford University, Oxford OX] 3PT, UK
1. Background The intervertebral disc has been studied for decades, and has been of particular interest since the paper of Mixter and Barr indicated that it could be a source of back pain. The causes of disc degeneration, the effect of disc degeneration on the biomechanical behaviour of the spine, and the relationship of disc degeneration to back pain have been of continuing interest. Thus, in discussing the contribution of scientific research to the understanding of back pain, we will concentrate on the disc and discuss what has been learned about its biology and biochemical composition over the past 25 years. We will also speculate about possibilities of future advances. By the time of the first meeting of the Society for Back Pain Research the anatomical structure of the disc was well known and changes with age and pathology had been described in great detail. There had also been detailed descriptions of the disc's embryological development. From a number of biochemical studies it had been shown that
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the disc was highly hydrated, particularly in the nucleus and that the water content of the disc decreased with age. It was also known that the major constituents were collagen, mucopolysaccharides (now called proteoglycans) and glycosaminoglycans, and that the concentrations and organisation of these components were different in the nucleus and annulus, with the annulus having more collagen and less glycosaminoglycan than the nucleus. Changes in composition with age and pathology had also been studied and showed that glycosaminoglycan concentrations fell with age, particularly in the nucleus, and were very low in degenerate discs. A review by Szirmai [1] summarises knowledge of the structure and composition of the disc at around the time the Society was founded. 2. Disc biochemistry
Over the past 25 years a major thrust of connective tissue research has been directed towards understanding the constituent macromolecules that make up the matrix as discussed in some recent reviews [2,3]. Some advances in knowledge with reference to the disc are outlined below.
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J. Urban / Journal of Back and Musculoskeletal Rehabilitation 9 (1997) 23-27
2.1. Collagen
Collagen is now known not to be a simple chemical species but consists of many (at present 18) genetically distinct molecules all including at least one region with a triple-helix. Eyre and Muir showed in the 1970s that the disc contained at least two different fibrillar collagens [4], type I and type II. Now at least seven different collagen types are known to exist in the disc [5] and the composition of these different collagens is known in detail at the protein and DNA level. Development of immunohistochemistry has enabled even minor components to be localized to specific sites; collagens III and VI for instance are found predominantly in a pericellular region [6]. Alternatively spliced forms of some of these collagens exist and this may be important in development [7]. However, little is known about changes in collagen in degenerate discs, apart from descriptions of the loss of lamellar and nucleus organisation. 2.2. Proteoglycans
The structure of the major proteoglycan of cartilage, aggrecan, has been delineated at the protein and DNA level over the last few decades and is now known in detail. Aggrecan was shown to be also the major proteoglycan of disc by Stevens et al. [8] in the 1970s. Several more recent studies have found that in the disc, aggrecan and the associated link protein degrade relatively soon after synthesis [9,10]. However, as long as the aggrecan fragments are retained, they maintain turgor in the tissue. Degenerate discs are associated with loss of aggrecan and hence a fall in swelling pressure and water content. Versican, a large proteoglycan present in tendon [11] and the small leucine-rich proteoglycans such as decorin, biglycan and fibromodulin are also found particularly in the annulus [12]. 2.3. Proteinases and inflammatory factors
Research has concentrated mainly on structural macromolecules but several classes of pro-
teinases, responsible for turning over and degrading connective tissue components have been found in the disc, some of these in active form [13-15]. Inhibitors to these proteinases have also been found. Although it has been shown that cultured disc slices can produce some classes of proteinases, it is not known if disc cells are responsible for producing those found in disc in vivo, nor how proteinase-inhibitor levels are regulated. 3. Biosynthesis and metabolism 3.1. Energy metabolism
Holm et al. showed about 15 years ago that though the cells required oxygen, disc metabolism was mainly anaerobic [16]. The cells thus produce high concentrations of lactate, which increases at the low oxygen levels found in the centre of the disc, thus explaining the high concentrations of lactic acid and low pH found in discs by Nachemson earlier [17]. Whether loss of nutrient supply can lead to degeneration as suggested by Nachemson at one of the first meetings of the Society is still unknown. 3.2. Biosynthesis
Apart from a few in-vivo studies on small mammals there had been virtually no studies on biosynthesis of matrix macromolecules until the last decade, mainly because of technical difficulties. Since then Johnstone and Bayliss and coworkers have studied biosynthesis of aggrecan and other proteoglycans in human discs in vitro and found changes with region and age, reflecting changes in composition. More recently, techniques have been developed for studying isolated disc cells [18] and results from these studies have pointed out the cellular heterogeneity of the disc. With these techniques it has also been possible to study regulation of biosynthesis; mechanical load, metabolite levels and the levels of growth factors and cytokines can all affect rates of biosynthesis and thus have the potential for altering tissue composition in the long-term.
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3.3. In-vivo animal studies An animal model developed by Osti et a1. [19], showed that an annulus tear could lead to disc degeneration over months; in many way the changes appeared to mimic those seen in human disc degeneration. The mechanism behind this is still unknown, however several laboratories are now using this model to investigate disc degeneration further [20]. Animals have also been used to investigate disc changes after exposure to environmental risk factors such as heavy loading [21] or smoking [22]. Further work on such models should enable the natural history of disc degeneration to be elucidated
4. Nerves in the disc The question whether nerves existed in the disc has been controversial for much of the past 25 years since histochemical methods for demonstrating the presence of nerve fibres were nonspecific. Recently specific antibodies against neuropeptides have been used to demonstrate conclusively the presence of sensory nerve endings in the outer few millimetres of the disc [23]. The density of the nerve endings is sparse in normal discs but increases in degenerate discs. These results indicate that the disc itself could be a source of pain. With this finding has come work indicating that cells from herniated discs under some culture conditions can produce cytokines and other inflammatory factors [24]. The interest in this process is growing since these factors could sensitize nerve endings in the disc and other spinal structures and thus facilitate pain production. 5. Genetic or developmental factors in disc degeneration For many years it has been suggested that there is a genetic predisposition to disc degeneration and back pain. Indeed it has been shown in dogs that there is a familial tendency to early degeneration-like changes in the disc. Recent studies in Finland, made possible by the compre-
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hensive data base on the Finnish population, have demonstrated a possible genetic link [25]. Factors affecting growth and development may also predispose individuals to back pain. For instance, Porter found that the width of the spinal canal was adversely affected by poor maternal nutrition [26]. 6. Imaging Over the past 25 years there have been major advances in imaging techniques with the development of cr scanning and MRI. The use of these techniques have provided remarkable views of the disc and surrounding structures and increased information available for diagnosls significantly. They have also provided a tool for physiological studies. Boos et a1. for instance use MRI images on a cohort of volunteers to show that during normal activities the disc loses around 20% of its fluid between morning and evening [27]. 7. Prospects for the future Since the SBPR started there have been tremendous advances in understanding both tissue biochemistry and cell and molecular biology. Application of these techniques to the disc have substantially increased information about its structure and further applications give hope for new and successful solutions to the problem of back pain. With advances in cell and molecular biology, the environmental and genetic factors leading to disc degeneration may soon be uncovered. Such information promises the possibility of prevention. Biological repair of degenerated and painful discs is another possibility. There have been considerable advances in inducing repair in articular cartilage, with some treatments already in clinical use and it is likely that this technology will also be applied to the disc once its cell biology is better understood. The use of gene therapy has been proposed and may also play a role in stimulating repair in the future. Advances in understanding the disc composition and the structure of its macromolecular constituents together with information available from differ-
J. Urban / Journal of Back and Musculoskeletal Rehabilitation 9 (1997) 23-27
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Table 1 Comparisons between costs to the NHS of back pain [28], osteoarthritis and kidney diseases. Expenditure for 1992/1993 in millions of pounds
Costs to NHS
Back pain
Osteoarthritis
Kidney failure
309.6
481.6
78.5
References
ent imaging techniques could lead to advances in chemonucleolysis which would minimise surgical interventions. The potential for prevention and relief of back pain thus appears promising. However, none of these advances will occur without considerable investment in scientific research and here the prospects look distinctly grim. The disc, despite the large costs of back pain, has never been an area which attracted scientific interest. Very little research has been carried out on the disc compared to other systems as shown in the following table which compares the direct NHS costs of three different disorders (Table 1) with the amount of scientific research into each as evident from a MEDLINE search (Table 2). The difference between interest in research into the biology of the kidney and that of the disc is staggering; there are even more papers on biomechanics of the kidney than biomechanics of the disc. With the fall in research funding in both Europe and the USA, the proportion of scientific work carried out on the disc is urtlikely to expand. Unless there is a substantial increase in the number of large and well-funded laboratories investigating the cell
Table 2 Research carried out into the intervertebral disc, articular cartilage and kidney between 1962 and October 1996. The research data comes from a direct MEDLINE search using the keywords shown and gives the number of papers in each search. Subject area
Intervertebral disc
Articular cartilage
Kidney
Metabolism MRI Proteoglycans Biomechanics
190 41
3101 162 1153 541
99404 388 333 184
77 118
biology and molecular biology of the disc, progress into understanding the basis of back pain or its treatment will be slow and the potential of new technologies will not be fulfilled.
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[23] Ashton K, Roberts S, Jaffray DC, Polak J, Eisenstein SM, Neuropeptides in the human intervertebral disc. J Orthop Res 1994;12:186-192. [24] Kang JD, Georgescu HI, Mcintyre-Larkin L, Stefanovic-Racic M, Donaldson WF, Evans CH, Herniated lumbar intervertebral discs spontaneously produced matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 1996;21:271-277. [25] Videman T, Battie MC, Epidemiology of Disc Disease. In: Wiesel SW, Weinstein IN, Herkowitz HN, Dvorak J, Bell G R, editors. The Lumbar Spine (I), Philadelphia: WB Saunders, 1996:16-27. [26] Porter RW, Development of the vertebral canal. In: Wiesel S, Weinstein IN, Herkowitz HN, Dvorak J, Bell GR, editors. The Lumbar Spine (2). Philadelphia: WB Saunders, 1996:716. [27] Boos N, Wallin A, Gbedegbegnon T, Aebi M, Boesch C, Quantitative MR imaging of lumbar intervertebral disks and vertebral bodies: influence of diurnal water content variations. Radiology 1993;188:351-354. [28] The burdens of disease: a discussion document. NHS Executive, 1996 (in press).