Toyone T, Takahashi K, Kitahara H, et al. Vertebral Bone-Marrow changes in degenerative lumbar disc disease. J Bone Joint Surg [Br] 1994;76-B:757-64.

The authors studied the end plate and vertebral bone marrow changes associated with degenerative lumbar disc disease seen on MRI in 75 patients and compared these findings with the mobility of L3-L4, L4-L5, L5-S1 levels and the corresponding histological studies. The authors concluded that MRI cannot provide information on mechanical parameters of bone remodelling but can demonstrate a clear correlation between marrow changes on T1-weighted images and the incidence of low back pain and segmental hypermobility.
Type A lesions were associated with thickened bony trabeculae and fibrovascular bone marrow, indicating injury and repair of the vertebral end plate. In Type B lesions, there was fatty replacement of the bone marrow. They hypothesise that the latter changes, common in late-stage degenerative disc disease, may represent the “restabilisation phase” described by Kirkaldy-Willis and Farfan in 1982.¹ The authors mention that they have used the term “segmental hypermobility” instead of the more ambiguous term “instability” because of the controversial nature of the latter. They provide interesting clinical information suggesting that abnormal remodelling of the vertebral osseous structures adjacent to disc degeneration in the presence of hypermobility can be associated with back pain.

References

1. Kirkadly-Willis WH, Farfan HF. Instability of the lumbar spine. Clin Orthop 1982;165:110-23.

Takahashi M, Haro H, Wakabayashi Y, et al. The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteine-3gene. J Bone Joint Surg [Br] 2001;83-B:491-5.

Takahashi M et al reviewed the important biological role of the enzymatic degradation of intervertebral disc (IVD) matrix by metalloproteinase-3 (MMP-3, stromelysin-1) in the production of IVD degeneration (Goupille et al¹). They discussed reports from the literature indicating that MMP-3 expression is induced in response to local conditions such as inflammatory and mechanical factors. They highlighted the fact that a common polymorphism in the promoter region of the human MMP-3 gene has been identified as being involved in the regulation of MMP-3 gene expression with the 5A (5 adenosine) 6A (6 adenosines) alleles (Ye et al²). The authors investigated the association between IVD degeneration in the elderly and polymorphism in the promoters region of MMP-3 gene. They concluded that 5A allele is a possible risk factor for acceleration of degenerative changes of the lumbar intervertebral disc in the elderly.
The findings of this article may well have practical clinical applications for the production of laboratory tests to identify the population at risk for lumbar disc degeneration.

References

1. Goupille P, Jayson MI, Valat JP, Freemont AJ. Matrix metalloproteinases: the clue to intervertebral disc degeneration? Spine 1998;23:1612-26.
2. Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Prelimanary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995;73:209-15.

Burke JG, Watson RWG, McCormack D, et al. Intervertebral discs which cause low back pain secrete levels of proinflammatory mediators. J Bone Joint Surg [Br] 2002;84-B:196-201.

Following the findings that painful degenerative intervertebral discs contain more nociceptive nerve endings in the end plates of the disc and in the nucleus pulposous than does a degenerative disc which does not cause low back pain,^1,2 Burke et al studied the production of inflammatory mediators in disc tissues in a similar group of patients. In a well designed clinical study, then compared the levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) in disc tissue from patients undergoing discectomy for sciatica (n=63) with those from patients undergoing fusion for discogenic low back pain (N=20) using an enzyme-liked immunoabsorbent assay. The statistical significance of the results of this study allowed the authors to conclude that the high levels of pro-inflammatory mediators found in disc tissue from patients with degenerative intervertebral disc associated with low back pain may be a major factor in the genesis of discogenic pain. Why certain intervertebral discs are associated with increased production of inflammatory mediators is currently unknown and needs to be investigated.

References

1. Coppes M, Marani E, Thomeer R, Groen RJ. Innervation of “painful” lumbar discs. Spine 1997;22:2342-9.
2. Brown M, Hukkanen M, McCarthy I, et al. Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease. J Bone Joint Surg [Br] 1997;79-B:147-53.

Philips FM, Reuben J, Wettzel FT. Intervertebral disc degeneration adjacent to a lumbar fusion. J Bone Joint Surg [Br] 2002;84-B:289-94.

Lumbar fusion induces alterations of stresses at adjacent, mobile, segments, predisposing them to accelerated degeneration and instability.¹ Philips et al in an interesting rabbit model experiment (28 rabbits) investigated disc degeneration adjacent to lumbar fusion. The rabbits underwent bilateral posterolateral intertransverse arthrodesis at L4-L5 and L5-S1 levels using methylmethacrylate and wire, in order to obtain immediate rigid stability and avoid the possibility of pseudarthrosis when using bone graft. Loss of the normal parallel arrangement of collagen bundles within the annular lamellae was observed in intervertebral discs adjacent to the fusion at three months. By six months, there was further disorganisation as well as loss of distinction between the lamellae themselves. By nine months, the structure of the disc had been replaced by disorganised fibrous tissue and annular tears were seen. Degeneration was accompanied by a decrease in the monomer size of prosteoglycans. An initial cellular proliferative response was followed by a loss of chondrocytes and osteochondral cells in the nucleous pulposus. Radiologically, narrowing of the disc space, endplate sclerosis and the formation of osteophytes at adjacent disc spaces were observed.
The authors support the theory that loss of the normal annular architecture in response to abnormal mechanical stresses may be an early stage in the degenerative process. They showed that disruption of the annular organisation preceded the formation of tears and clefts, thus suggesting that tears and rupture occur in the structurally altered annulus rather than representing an inciting injury in the process of disc degeneration.
The merit of this experiment lies on the fact that this rabbit model reproduced the pathological and biomechanical features of human disc degeneration without requiring an artificial injury (annulotomy, chemical injury, facet excision to produce torsional injury) to the disc to initiate the process of degeneration. The authors are to be commended for their landmark experiment.

References

1. Lee CK. Accelerated degeneration of the segment adjacent to a lumbar fusion. Spine 1988;13:375-7.
2. Smith JW, Walmsley R. Experimental incision of the intervertebral disc. J Bone Joint Surg [Br] 1951;33-B:612-25.

Sugimori K, Kawaguchi Y, Morita M, Kitajima I, Kimura T. High-sensitivity analysis of C-reactive protein in young patients with lumbar disc herniation. J Bone Joint Surg [Br] 2003;85-B:1151-4.

In a clinical study of 101 patients (48 patients with lumbar disc herniation and 53 normal controls), Sugimori et al substantiated the findings of others that there is a positive correlation between high sensitivity C-reactive protein (hsCRP) and lumbar disc herniation. Furthermore, they demonstrated that patients with higher pre-operative levels of hsCRP may have a poorer outcome. Based on published reports,^1,2 the authors further advanced the concept that macrophages and other inflammatory cells in herniated disc tissue produce inflammatory mediators such as interleukin-1 (IL-1) interleukin-6 (IL-6), tumour necrosis factor (TNF)-a, intercellular adhension molecule-1 (ICAM-1), lymphocyte function associated antigen (LFP-1) basic fibroplast growth factor (bFGF), prostaglandin E2 (PGE2) leukotriene B4 (LTB4), thromboxane B2 (TxB2) phospholipase A2, nitric oxide (No) and matrix metalloproteinase (MMPS). These cytokines and particularly pro-inflammatory cytokine, such as IL-6 and Il-1, are largely responsible for increasing the cerum CRP.
Elevated CRP in lumbar disc herniation and its correlation with inflammatory cytokines, (IL-6, IL-1) are indicative of an ongoing inflammatory process in the degenerative disc herniation.
Therefore, it is reasonable to assume that inflammation may play a dominant role in disc degeneration perhaps as a result of trauma or as independent aetiologic entity, that may weaken the disc to yield to subsequent abnormal loadings.

References

1. Saal JS, Franson C, Dobrow R, et al. High levels of inflammatory phospholipase A2 activity in lumbar disc herniations. Spine 1990;15:674-8.
2. Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases nitric oxide, interleukin-6 and prostaglandin E2. Spine 1996;21:271-7.

Matsui Y, Mizza SK, Wu J.-J., et al. The association of lumbar spondylolisthesis with collagen IX tryptophan alleles. J Bone Joint Surg [Br] 2004;86-B:1021-6.

Genetic predisposition to disc degeneration is gaining momentum. Most studies consider collagen defects particularly those of Type IX collagen. Type II collagen consists of three genetically distinct chains: a1(IX), a2(IX), a3(IX). Type IX collagen is important for the maintenance and normal development of hyaline cartilage, as a structural component of the matrix function and an interfacial protein in covalent cross-linkage to the surface of type II collagen fibril. Mutation in type IX collagen genes caused intervertebral disc degeneration in mice.
Matsui et al tried to determine whether a certain subset of degeneration of the lumbar spine is specifically associated with the tryptophan polymorphism. They performed a prospective case control study of 107 patients who underwent surgery of the lumbar spine. What prompted the authors to carry out this investigation was a Finnish study^1,2 demonstrating that patients with type IX collagen genes linked to polymorphic variants that encode tryptophan (at position 326 of the a2 (IX) chain - Type 2, or at position 103 of the a3 (IX) chain – Type 3) have an increased risk of lumbar disc disease and chronic sciatica. Patients were assigned to one of the following clinical categories: fracture, disc degeneration, disc herniation, spinal stenosis without spondylolisthesis and spinal stenosis with spondylolisthesis.
This study indicates that tryptophan polymorphisms predispose carriers to the development of symptomatic spinal stenosis associated with spondylolisthesis (odds ratio 0.81, 95% CI 1.47 to 41.95) requiring surgery. Of the 11 tryptophan–positive patients, eight had spinal stenosis with spondylolisthesis and three had disc herniation. The presence of the tryptophan allele was significantly associated with African-American or Asian designation for race (odds ratio 4.61, 95% CI 0.63 to 25.35). Since they do not have control information on the frequency of the Type 2 and Type 3 alleles in the population from which the patients were drawn, the authors cannot assess whether the Type (+) allele is associated with an increased risk of lumbar disc disease in general.
The risk of degenerative changes leading to spinal stenosis and spondylolisthesis, possibly, is much higher in Type T (+) than in Type (-) individuals. Furthermore, Type (+) patients are more likely to develop symptoms which require surgical treatment. If these results are reproduced by others, it would provide a great contribution to the clinical assessment of patients with low back pain.

References

1. Paassilta P, Lohiniva J, Goring HH, et al. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 2001;285:1843-9.
2. Annunen S, Paassilta P, Lohiniva J, et al. An allele of COL9A2 associated with intervertebral disc disease. Science 1999;285:409-12.

Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y. The pathogenesis of discogenic low back pain. J Bone Joint Surg [Br] 2005;87-B:62-7.

Is degeneration of intervertebral disc (IVD) responsible for low back pain (LBP)? Is discogenic LBP a distinct clinical entity resulting from specific pathological changes in the IVD? If so, what are the specific histological disc changes that can be used as evidence to explain the pathogenesis of discogenic pain? It is difficult to answer these questions.
In a well designed clinicopathological study from Beijing, Peng et al harvested 19 lumbar IVD from 17 patients suffering from LBP during posterior lumbar interbody fusion. The diagnosis of LBP was based on discographic studies. The authors investigated the histopathological features of the IVD and assessed the immunoreactive response of neurofilaments (NF 200) and neuropeptides such as substance P (SP) and vasoactive-intestinal peptide (VIP) in the nerve fibres. They compared these findings with those of a similar investigation carried out in 12 physiologically ageing discs and 10 normally control discs. The following observations were made: (a) the distinction between the nucleus pulposus and the inner annular fibrosus is blurred in the ageing IVD and disappears in the painful IVD; (b) in the matrix of the nucleus pulposus of the normal disc there are sparse collagen fibres with a single cartilage cell or an island of a few cells surrounded by capsule; (c) in the ageing disc there is increased density of the nucleus pulposus matrix and the formation of clusters of chondrocytes, whereas in the painful IVD the fibrosis is denser in the matrix and the round chondrocytes are transformed into oval fibroblasts. The most interesting observation was the fact that there were distinguishing histological changes in the painful IVD characterised by the formation of a vascularised granulation tissue zone extending from the nucleus pulposus to the outer part of the annulus fibrosus along the edges of the tears seen on CT scan after discography. The authors also observed the growth of nerves deep into the annulus fibrosus and nucleus pulposous, mainly along the zone of granulation tissue in the painful discs.
The values of SP-, NF- and VIP-immunoreactive nerve fibers in the painful discs were more extensive than in the control discs. According to the authors, this study suggests that the zone of granulation tissue with extensive interaction along the tears in the posterior part of the disc may be responsible for causing discogenic LBP that can also be provoked mechanically by discography.
Previous studies on the relationship between patients with low back pain and innervation of discs was made on specimens harvested from the anterior aspect of painful discs, in which tears or fissures in the annulus fibrosus are rarely seen on discography and therefore are not representative of pain provoked by discography.^1,2
The strength of this paper is that it demonstrates the distinct pathophysiological changes along the course of IVD tears in the posterior annulus as revealed by CT scan discography and coinciding with concordant pain when provoked during discographic studies. The weakness of this study is the absence of effectiveness of fusion to alleviate pain. The latter would have added further support to the controversial issue of the clinical value of discography and would have supported the discogenic origin of LBP. This research contradicts Eugene Carragee’s clinical study.

References

1. Freemont AJ, Peacock TE, Goupille P, et al. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 1997;19:350.
2. Coppes MH, Marani E, Thomeer RT, Groen GJ. Innervation of “painful” lumbar discs. Spine 1997;22:2342-9.

Aihara T, Takahashi K, Ogasawara A, et al. Intervertebral disc degeneration associated with lumbosacral transitional vertebrae: a clinical and anatomical study. J Bone Joint Surg [Br] 2005;87-B:687-90.

Aihara et al performed clinical and cadaver studies to demonstrate the influence of vertebral hypermobility on the incidence and severity of intervertebral (IV) disc degeneration.
In the clinical study, they used MRI to investigate 52 patients with lumbosacral transitional vertebra. They observed that the lumbar discs, immediately above the transitional vertebra, were significantly more degenerative than those between the transitional vertebra and the sacrum, which in turn, were significantly less degenerative than those at other levels. The cadaver study comprised 70 cadavers.
Morphological investigations showed that the iliolumbar ligament, at the level immediately above the transitional vertebra, is thinner and weaker than in cadavers without a lumbosacral transitional vertebra. This supported the conclusion of previous investigations, with a different model design, that instability of the vertebral segment above the transitional vertebra, when caused by a weak iliolumbar ligament, could lead to disc degeneration and occurs earlier than at other disc levels. Furthermore, when there is stability between transitional vertebra and the sacrum (provided by the either articulation or bony union between these two structures) it may protect the disc from further degeneration in the long term.
Although this study indicates that excessive mechanical stresses on the intervertebral disc from hypermobility may contribute to earlier and more severe disc degeneration, it is unfortunately not corroborated by the respective biomechanical studies.

References

1. Aihara T, Takahashi K, Ono Y, Moriya H. Does the morphology of the iliolumbar ligamnet affect lumbosacral disc degeneration? Spine 2002;27:1499-503.
2. Garvin PJ, Jennings RB. Long-term effects of chymopapain on intervertebral discs of dogs. Clin Orthop 1973;92:281-95.

Ranson CA, Kerslake RW, Burnet AF, Batt ME, Abdi S. Magnetic resonance imaging of the lumbar spine in asymptomatic professional fast bowlers in cricket. J Bone Joint Surg [Br] 2005;87-B:1111-16.

Fast bowling was reported to be associated with lumbar intervertebral disc degeneration, with a prevalence of 65% at a mean age of 17.9 years.¹ In an injury surveillance study of professional fast bowlers in cricket, Ranson et al examined the MRI appearance of the lumbar spines of 36 asymptomatic professional fast bowlers and 17 active control subjects. They observed that fast bowlers had a relatively high prevalence of multi-level degeneration of the lumbar discs and a unique pattern of stress lesions of the pars interarticulares on the non-dominant side.
They found that a high proportion (50%) of bowlers in this study who had chronic stress reaction and a subtotal stress fracture had normal appearance and height of the intervertebral disc and could continue to bowl. However, if they continued to do so with bilateral stress fractures they could precipitate severe disc degeneration at that spinal level. This suggests that disc degeneration is not a necessary precursor to lumbar stress injury and that excess segmental motion caused by an un-united pars fracture can precipitate disc degeneration. As might be expected, the authors concluded that the relationship between severe disc generation, pain and dysfunction remain unclear and further prospective studies are required.
This paper thus supports the concept that mechanical factors (most likely torsional forces), in highly stress demanding sports, can predispose to disc degeneration.

References

1. Elliott BC, Davis JW, Khangure MS, Hardcastle P, Foster D. Disc degeneration and the young fast bowler in cricket. Clin Biomech 1993;8:227-34.

Lee DY, Ahn Y, Lee SH. The influence of facet tropism on herniation of the lumbar disc in adolescents and adults. J Bone Joint Surg [Br] 2006;88-B:520-3.

Farfan and Sullivan¹ put forward the concept that asymmetry of the lumbar facet orientation may predispose to disc herniation. Subsequently, this theory was supported by some and challenged by others. Because of these conflicting reports, this Korean study studied this premise in 140 adolescents and 111 adults by measuring the facet tropism at L3-L4, L4-L5 and L5-S1 levels on CT scans. They found that there was no significant statistical difference in facet tropism between the herniated and the normal discs in both the adolescent and adult groups, except at the L4-L5 level in adults. They also concluded that facet tropism did not influence the development of herniation of the lumbar disc in either adolescents or adults. I am a bit sceptical about the last statement since it contradicts the finding reported by the authors that at L4-L5 levels there was statistical difference (p < 0.001-student’s t-test) between L4-L5 facet tropism and disc herniation. Unfortunately, this paper does not provide biomechanical data showing whether facet tropism is associated with abnormal or excessive loadings on the intervertebral disc.

References

1. Farfan HF, Sullivan JD. The relation of facet orientation to intervertebral disc failure. Can J Surg 1967;10:179-85.

Takebayashi T, Cavanaugh JM, Kallakuzzi S, Chen C, Yamashita Y. Sympathetic afferent units from lumbar intervertebral discs. J Bone Joint Surg [Br] 2006:88-B:554-7.

Takebayashi et al based on findings by others demonstrating that (a) in rats the sinuvertebral nerves proceed into the paravertebral sympathetic trunk though the rami communicates, (b) the innervation of the L5-L6 intervertebral discs and adjacent tissues is from L1 and L2 dorsal root ganglia through the paravertebral sympathetic trunk (c) and that patients suffering from lower lumbar back pain, experienced relief of pain when they underwent infiltration of the L2 nerve roots with lidocaine,¹ decided to further investigate the pathomechanism of discogenic low back pain in the laboratory. Using neurophysiological monitoring in rats the authors studied the sympathetic afferent discharge originating from the L5-L6 disc via L2 root. Their experiment indicates that mechanical stimulation of the lumbar discs may not always produce pain, whereas inflammatory changes may cause the disc to become sensitive to mechanical stimuli resulting in nociceptive information being transmitted as discogenic low back pain to the spinal cord through the lumbar sympathetic trunk. They concluded that this animal experiment may partly explain the variation in human symptoms of degenerative discs. They commented that these findings corroborate well with Schaible et al² who reported the mechanically insensitive afferent nerve units of the joint may become responsive in the presence of inflammation.

References

1. Nakamura S, Takahashi K, Takahashi Y, Yamagata Y, Moriya H. The afferent pathways of discogenic low-back pain: evaluation of L2 spinal nerve infiltration. J Bone and Joint Surgery [Br] 1996:78-B;606-12.
2. Schaible HG, Schmidt RF. Effects of an experimental arthritis on the sensory properties of fine articular afferent units. J Neurophysiol 1985:54:1109-22.

Conclusion
After reading these papers, one gets the impression that there are several reasonably valid and diverse concepts concerning the pathophysiology of disc degeneration. It is reasonable to assume that all the different factors presented may behave independently as initiators or as promoters or both in the process of disc degeneration. It is also conceivable that at some point in time different other factors may have a variable influence in disc degeneration that was initially provoked by a different cause, i.e. trauma may initiate inflammation in the process of disc degeneration; or inflammation as a result of molecular changes may be accelerated with superimposed abnormal loadings. Finally, in certain situations genetic predisposition may influence all mechanisms of disc degeneration. However, the validity of these relationships needs to be substantiated in definitive scientific studies.