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Rheumatology Advance Access published online on October 14, 2008
Rheumatology, doi:10.1093/rheumatology/ken396
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review

The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain

A. J. Freemont1

1Tissue Injury and Repair Research Group, Research School of Clinical and Laboratory Sciences, University of Manchester, Manchester, UK.

Correspondence to: A. J. Freemont, Tissue Injury and Repair Research Group, Research School of Clinical and Laboratory Sciences, Stopford Building, University of Manchester, Manchester M13 9PT, UK. E-mail: tony.freemont{at}manchester.ac.uk


   Abstract
Top
 Abstract
Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 
In 2007, three times as many peer reviewed publications covering the biology and biotherapeutics of intervertebral disc (IVD) disease appeared in the literature than in 1997. This is testimony to the upsurge in interest in the IVD, mainly driven by the openings that modern molecular pathology has generated to investigate mechanisms of human disease and the potential offered by novel therapeutic technologies to use data coming from these studies to positively influence chronic discogenic back pain and sciatica. Molecular pathology has shown IVD degeneration, a major cause of low back pain, to be a complex, active disorder in which disturbed cytokine biology, cellular dysfunction and altered load responses play key roles. This has translated into a search for target molecules and disease processes that might be the focus of future, evidence-based therapies for back pain. It is not possible to describe the totality of advances that have been made in understanding the biology of the IVD in recent years, but in this review those areas of biology that are currently influencing, or could conceivably soon impinge on, clinical thinking or practice around IVD degeneration and discogenic back pain are described and discussed.

KEY WORDS: Intervertebral disc, Back pain, Pathobiology, Degeneration


   Introduction
Top
 Abstract
 Introduction
The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 
It is estimated that more than half the population will experience significant low back pain (LBP) during their lives [1]. LBP is a major cause of morbidity and impacts considerably on the economy, both through loss of work (~15% of all sickness leave in the United Kingdom) and the cost of health care and societal support for the affected individual and their family [2, 3].

Although an important public health issue, the pathogenesis of LBP is poorly understood. Most is thought to arise from disturbances in the lumbar spine and associated structures. Studies examining the problem from different directions (e.g. examination of volunteers [4] and patients [5], imaging investigations [6], trials of intervention [7]) have produced evidence implicating the intervertebral disc (IVD) in a significant proportion (at least 40%) of cases of chronic back pain, leading to the use of the term ‘discogenic back pain’.

From the work that has been carried out to date two processes stand out as being important in the origins of discogenic back pain, disc degeneration and nociceptive nerve ingrowth into the normally aneural IVD.

Only in the last 10–15 yrs have the mechanisms underlying human IVD degeneration been studied in any detail, but the arrival of molecular pathology and similar techniques for examining disease mechanisms in human tissue (e.g. immunohistochemistry [8], in situ zymography [9], in situ hybridization [10] and quantitative image analysis [11]) and the advent of biotherapeutics [12], stem cell therapy [13] and tissue engineering [14] have brought both methods for and reasons to investigate IVD degeneration.

During these studies it became evident that there was vascular ingrowth into the degenerate IVD and that in painful degenerate IVD the vessels were accompanied by nociceptive nerves. Further investigation is required, but if it transpires that nociceptive nerve ingrowth is a major cause of discogenic back pain, the processes driving this ingrowth could become key therapeutic targets for its management.

To understand the pathology and pathogenesis of IVD degeneration and discogenic back pain, it is first necessary to have an overview of the normal IVD and IVD cell function.


   The normal IVD
Top
 Abstract
 Introduction
 The normal IVD
'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 
The IVD, adjacent two vertebrae and their posterior elements are described as the ‘motion segment’. The nature of the specialized matrix of the IVD allows movement (e.g. twisting and bending), offers resilience under compression, and is key to the ‘spacer’ function of the IVD necessary for generating the optimal biomechanical environment within the motion segment.

The central component of the IVD [the nucleus pulposus (NP)], has a matrix that consists of type II collagen and the proteoglycan aggrecan in a ratio of 1 : 20 (cf. articular cartilage 1 : 2) [15]. Aggrecan is highly hydrophilic, imbibing water with such avidity that it generates a swelling pressure sufficient to force apart the vertebral bodies.

The matrix of the NP is maintained by the cells within it. They have a chondroid phenotype which is characterized by the expression of the matrix molecules aggrecan and type II collagen and the regulatory molecule, Sox9 [16]. There is now developing evidence that the cytokine IL-1 is important in normal IVD cell function [17].

The NP is confined above and below by the end plates of the vertebral bodies and circumferentially by the fibres of the annulus fibrosus (AF).

The end plates consist of a layer of articular cartilage (cartilage end plate) in contact with the NP and separating it from the cortical bone of the vertebral body (bony end plate). The cartilage and bony end plates are together known as ‘the end plate’ (EP). The EP gives the resilience that prevents the load transmitted through the IVD fracturing the bone of the vertebral body.

The swelling pressure of the NP is resisted by tension in the type I collagen fibres of the AF. The AF consists of a number of lamellae. In each, the collagen fibres are parallel to one another and run diagonally between the vertebrae. The fibres in each lamella run at an angle (120°) to those in the two immediately adjacent lamellae such that in rotational movements some fibres are put into tension and others become slack. At rest the balance between the swelling pressure in the NP and the tension in the AF maintains the distance between adjacent vertebral bodies.

The matrices of all three structures (NP, AF and EP) are highly regulated by the cells they contain through continuous matrix breakdown and synthesis.

With the exception of the outermost AF, the normal IVD is both avascular and aneural.


   ‘Degeneration’ of the IVD
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 
The tissue changes of degeneration are increased breakdown of matrix, altered matrix synthesis (consisting largely of a change from type II to type I collagen synthesis and decreased synthesis of aggrecan), cell loss through apoptosis and in situ replication of surviving cells to form clusters [18–20]. The process extends to the AF largely as a result of altered loading consequent upon reduced separation between vertebrae (‘loss of disc height’) as the amount of aggrecan and the swelling pressure of the NP fall. In this setting, the normal balance between forces generated in the NP and AF is lost, resulting in decreased tension in the collagen fibres in the AF, which promotes shock loading at the enthesis during normal movement, leading to microtrauma and pain. The microtrauma damages both the AF and the bone into which the fibres of the AF insert, allowing blood vessels and nerves a route into the IVD [21]. Similar changes occur in the EP as a result of fracture. When the spacing effect of the normal NP is lost and the vertebral bodies approximate to one another, abnormal movement and loading occurs throughout the entire motion segment causing traumatic damage to the facet joints and other structures [22, 23].

Although dysfunction of the motion segment is caused by adverse changes in the matrix of the IVD, these changes are mediated by disturbances in the biology of the cells of the NP, AF and EP [24]. These have been the focus of much of the recent study of degeneration.


   New advances in understanding the altered cell biology of IVD degeneration
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 
Five major factors influence IVD cell function in health and degeneration:

  1. Diffusion of nutrients and oxygen across the IVD matrix.
  2. Soluble regulators of cell function.
  3. Genetic influences.
  4. Ageing and senescence.
  5. Mechanical load.

Diffusion of nutrients and oxygen across the IVD matrix
Cells of the IVD receive oxygen and nutrients by diffusion across the discal matrix. The outer AF probably gains its nutrients from the local vasculature but the remainder of the IVD is nourished from the bone marrow. As the lower lumbar discs are nearly 1 cm thick, the diffusion pathway to cells in the centre of the disc is long. Thus, the cells are believed to be adapted to function in an environment that is relatively oxygen and nutrient poor [25].

There is strong evidence that reduced blood flow to the margins of the IVD is associated with early and established degeneration. This may occur because of changes in the local vasculature (e.g. those initiated by smoking) or by disturbance of the physical structure of the EP [26, 27]. Whilst this might explain the cell changes that initiate degeneration, the evidence for this still needs to be fully tested and any hypothesis linking hypoxia to disc degeneration will need to explain the vascularization of the IVD that occurs in progressive degeneration [28].

This remains a very interesting field of research, particularly as this is one area of research endeavour that might shed some light on the still elusive events that initiate degeneration.

Soluble regulators of cell function
IL-1
There is accumulating evidence that both isoforms of the pleiotropic cytokine IL-1 (IL-1{alpha} ad IL-1β) are the normal regulators of IVD cell function and that IL-1 effects are controlled in this tissue as in others by synthesis of IL-1 through IL-1 converting enzyme (ICE), and balanced production of the activating receptor (IL-1RI), the exported decoy receptor (IL-1RII) and the inhibitor of IL-1: IL-1 receptor antagonist (IL-1Ra) [17].

In degeneration, there is a breakdown in IL-1 regulation with increased production of IL-1 isoforms by native disc cells associated with a failure to up-regulate IL-1Ra. This imbalance in the IL-1 system has been shown to be able to induce all the tissue changes associated with degeneration. These include:

  • Up-regulation of zinc-based matrix degrading enzymes, notably MMPs and ADAMTSs [20, 29–32].
  • Abnormal synthesis of aggrecan and collagen II and their replacement by collagen I [20, 33].
  • Angiogenesis [34, 35].
  • Neuronogenesis [36].
  • Apoptosis of native IVD cells [37].
Furthermore, exogenous IL-1Ra applied to IVD cells and human tissue explants will reverse the molecular pathology of degeneration [38–40].

The factors initiating the imbalance in the IL-1 system are unknown. Load has been implicated [41], but a role has not been proved. Interestingly genetic epidemiology has shown an association between back pain, IVD degeneration and the inheritance of specific genes of the IL-1 family [42–44], raising the possibility that suboptimal function of the protein products of these genes might pre-dispose to the development of IVD cell dysfunction. This is clearly not the whole story as non-back pain patients express these haplotypes and not all the discs in those expressing these genes become degenerate.

TNF-{alpha}
This has been discovered within the degenerate IVD and to a lesser extent the normal disc [45]. It is particularly expressed by the cells in prolapsed disc tissue.

In animal models, NP tissue has been applied directly onto spinal nerve roots in the epidural space [46]. This resulted in functional, vascular and morphological abnormalities of the nerve root, which were often followed by intraradicular fibrosis and nerve fibre atrophy. Extrapolating from the finding that TNF was expressed by cells in disc protrusions and that tissue found in prolapsed discs induced nerve damage, it was hypothesized that TNF might be the chemical mediator of discogenic radiculopathy. It was subsequently demonstrated that TNF-{alpha} applied to nerve roots caused vascular and radicular abnormalities similar to those seen following application of NP tissue [47], implicating TNF-{alpha} in nerve root damage and sciatic pain. Furthermore, application of TNF-{alpha} blockers [48] prevented the processes and symptoms. It was therefore hypothesized that TNF-{alpha} blockade might have a therapeutic role in sciatic pain [49]; however, such studies as have been performed using anti-TNF in patients with back pain have been less encouraging than might have been hoped [50]. An alternative explanation for the role of TNF-{alpha} in back pain comes from a recent study in the TNF-{alpha}-deficient mouse which has provided evidence that TNF-{alpha} can induce sensory nerve growth into the IVD [51], which is of considerable interest as it has been previously noted that nerve ingrowth is a feature of the painful degenerate IVD [52].

More recently, TNF has been implicated in the catabolic processes leading to matrix degradation in the degenerate IVD [53, 54]. The data around this are inconsistent. For instance, whilst there is no question that with increasing degrees of degeneration IVD cells exhibit increased TNF-{alpha} expression [55], the IVD cells that would be the putative target do not express its receptor [56], and anti-TNF does not inhibit in situ matrix degrading activity [40].

Other cytokines implicated in IVD catabolism
Other cytokines have been described in the degenerate IVD that could influence matrix breakdown [57, 58] but a precise role for them has yet to be discovered.

TGF-β superfamily
Inarticular cartilage members of the TGF-β superfamily are anabolic. Does this also apply to the IVD? In what surely will turn out to be a seminal paper on several fronts, TGF-β delivered by gene therapy was shown to increase aggrecan production by rabbit NP cells [59]. Others have shown that TGF-β can cause NP cell proliferation [60] and the formation of NP-like cells from mesenchymal stem cells [61].

However, current interest is focused not on TGF-β itself, but on other members of the TGF-β superfamily, and in particular the bone morphogenetic proteins (BMPs) [62, 63]. Of these, BMP-7 [osteogenic protein-1 (OP-1)] has received particular attention [64]. Preliminary data indicate that it may be a potent anabolic agent in regenerating the degenerate IVD.

Therapeutic implications
Importantly, with the advent of molecular medicine, cytokines and cytokine regulation pathways have the potential to be key therapeutic targets, as has happened in rheumatoid disease and OA. Although still relatively nascent, there is no doubt that the next few years will see increasing research focused on translating our understanding of molecular pathways underlying degeneration into novel therapies for managing discogenic pain [65] through prevention of progression or reversal of the pathology of degeneration. The greatest challenge, as in all areas of regenerative medicine that try to restore normal tissue within a disease system, is normalizing the biology of the diseased tissue ‘niche’ in which regeneration is being attempted. In this respect, normalizing the cytokine environment alone is clearly insufficient, and other factors such as abnormal load, and altered nutrient and metabolite transport, will need to be addressed in concert.

Genetic influences
Twin and other studies have shown that a significant proportion of IVD degeneration cases can be explained on the basis of genetic factors [66, 67]. Quite what those factors are has yet to be properly determined. However, a number of genetic associations have been reported over the last 20 yrs but only a few have been replicated convincingly. Of those molecules investigated, only VDR [68] and collagen IX [69] polymorphisms have been consistently associated with degeneration in reasonably sized populations. Other candidate genes linked to degeneration of the IVD include: collagen I {alpha}1 [70], interleukin-6 [71], aggrecan [72], MMP 3 [73], thrombospondin, cyclo-oxygenase, TIMP1 [74], cartilage intermediate layer protein [75] and IL-1 family members, as described earlier.

A better understanding of the significance of these findings can only come from a more thorough functional analysis of these polymorphisms within the context of the molecular pathology of the degenerate IVD.

Ageing and senescence
The nature of collagenous tissues is such that their physical properties change with time and age consequent upon progressive internal cross-linking of matrix molecules and the nutritional status of these poorly vascularized tissues. With age, these changes lead to modifications in collagen and proteoglycan composition of the IVD [76]. As the incidence of discal degeneration also increases with age, distinguishing ‘normal ageing’ from ‘disease’ becomes paramount [77]. This is complicated by the high frequency of disc degeneration at some spinal levels (e.g. L3-4, L4-5 and L5-S1), making the definition of ‘normality’ problematic.

Disc cell numbers and viability decrease in degenerate IVD. This has been attributed to apoptosis and, more recently, cellular senescence. Senescent cells lose their ability to divide but are viable and synthetically active, although gene expression is different from that in normal cells. The accumulation of senescent cells in vivo with age, together with their changed pattern of gene expression implicates cellular senescence in ageing and age-related pathologies [78] of other chondroid tissues such as articular cartilage in OA [79], where chondrocyte senescence correlates with disturbed matrix homoeostasis. This has raised the possibility that the changes seen within the diseased IVD are also senescence related.

There are two types of senescence: replicative senescence (RS) and stress-induced premature senescence (SIPS) [80]. RS is generally regarded as the result of telomere shortening accumulated as cells undergo repeated cell divisions, whereas SIPS occurs in response to stress-inducing factors such as exposure to cytokines or oxidative stress [81]. Certain cellular changes indicative of senescence are shared by RS and SIPS including: growth arrest, a large, flat cell morphology with increased staining for senescence-associated β-galactosidase (SA-βgal) and increased expression of cell cycle inhibitors.

The investigation of cellular senescence within human IVD is a relatively new area of research. In 2006 [82] and 2007 [83], two groups showed increased staining for SA-βgal in cells from prolapsed and degenerate IVD when compared to non-degenerate discs. A more comprehensive study of senescence biomarkers has recently been described [84]. This showed that: mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration; and expression of the cell cycle inhibitor p16INK4a protein (which is up-regulated during cellular senescence) increased with both subject age and degeneration, indicating that degeneration is a form of accelerated, tissue-specific cellular senescence. Furthermore, the study showed a direct relationship between expression of p16INK4a and the genes for two matrix degrading enzymes, MMP-13 and ADAMTS5, important in IVD degeneration [8, 20]. Whilst this might be an epiphenomenon, it might also link senescence and a catabolic phenotype.

Mechanical load
There is increasing evidence that load has a profound and fundamental influence on the biology of IVD cells [41] and, indeed that ‘normal’ mechanical loading is essential for maintaining a normal phenotype [85, 86]. Excessive spinal loading (e.g. as caused by lifestyle and increased body weight [87]) can lead to the development of the radiological and biochemical features of degeneration. Not only does excessive load lead to changes in the IVD but so too do other factors such as significant traumatic injury (e.g. EP fracture) [18] and scoliosis [88], which reduce or alter the load in other ways.

The precise mechanisms linking load and cell function in the IVD are poorly understood. However, there is increasing interest in mechanotransduction (the science that investigates the relationships between load, load recognition, intracellular signalling pathways, gene transcription and cell function, including regulation of extracellular matrices), which is gradually aiding an understanding of how the excellent work on the altered mechanical environment in the IVD that causes [89] and is caused by [90] degeneration, translates into altered cell and matrix biology [91] and can be employed in therapeutic regeneration [92]. This is likely to become a key area of IVD research in the next 5 yrs.


   Nerve ingrowth
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
Clinical...
 Acknowledgements
 References
 
A factor that has been a constant finding in the analysis of excised painful IVD has been the presence of nerves and blood vessels within the usually aneural and avascular tissues of the IVD. Generally, nerve and vessel ingrowth into usually aneural and avascular tissues can come about as a consequence of either loss of anti-angiogenic/-neuronogenic factors naturally present in avascular and aneural tissues or local production of angiogenic and neuronogenic factors in disease. It transpires that both processes might be at work in disc degeneration.

In 1997, two groups [52, 93] described ingrowth of nociceptive nerves into the degenerate IVD. This was based on identifying nerve fibres using a combination of nerve stains in histological sections of IVD. These nerves have the shape of nociceptive nerves and express GAP43, a marker of nerve growth, and substance P, a nociceptor (and vasoregulatory) neurotransmitter.

There have been a number of studies evaluating the mechanisms leading to nerve ingrowth. They can be summarized as falling into three groups. Nerve ingrowth: associated with angiogenesis; induced by an alteration in IVD matrix biology; and initiated by altered IVD cell function.

Angiogenesis-associated nerve ingrowth
Nerves growing into degenerate IVD do so in physical association with ingrowing blood vessels [94]. In the current state of knowledge, it would appear that the nerves growing into the disc initially have a vasoregulatory role, but at some stage and for unknown reasons they send off nociceptive shoots into the disc tissue. During angiogenesis, endothelial cells of vessels growing into the IVD synthesize the neurogenic stimulator, nerve growth factor (NGF), one of a family of neurotrophins [95]. Furthermore, the accompanying nerves expressed the high-affinity receptor for NGF, TrkA, a phenomenon entirely commensurate with a vasoregulatory role for nerves accompanying blood vessels.

An important aspect of these studies is that nerves with the structure and biology of nociceptive nerves are only seen in IVD that had been classified clinically as ‘pain level discs’. By this it is usually meant that insulting these discs (e.g. by discography or direct probing) specifically reproduces the patient's symptoms of back pain and/or sciatica. IVD showing similar degrees of degeneration but that did not come from ‘pain levels’ do not show nerve ingrowth.

Altered matrix biology and nerve ingrowth
In some very elegant experiments, Johnson and co-workers [96] examined the in vitro effects of aggrecan removed from normal human AF and NP had on neurite outgrowth. They showed that aggrecan derived from normal IVD inhibited the growth of neurites, but that aggrecan that had been deglycosylated to make it more akin to that found in the degenerate IVD had a reduced inhibitory effect. This implies that normal aggrecan is an inhibitor of nerve ingrowth into the IVD, and that in degeneration nerve ingrowth may occur as a consequence of changed aggrecan biology. Aggrecan from both the AF and NP were inhibitory but perhaps a little unexpectedly that from the AF was more inhibitory.

Altered IVD cell function
In a similar series of experiments, Johnson et al. [97] have also examined the effects of cells derived from normal and degenerate IVD on neurite outgrowth. They found that the normal inhibition of neurite outgrowth by aggrecan could be reversed by cells derived from degenerate IVD. The extent of the effect was related to the number of IVD cells. Conditioned media had no such effect.

Overview
Overall, current data indicate that normal IVD matrix prevents nerve ingrowth into the IVD, but that in degeneration changes in the structure of aggrecan, coupled with altered IVD cell biology lead to nerve ingrowth into pain level IVD and that this is enhanced by the production of neurogenic cytokines during neovascularization of the degenerate IVD.


   Clinical implications/applications
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
Acknowledgements
 References
 
At the present time, therapy for discogenic back pain is largely empirical and aimed at relieving symptoms rather than addressing the underlying disease mechanisms. The continually increasing burden of disease and the patient experience suggest that this approach has limited success. It could be argued that therapeutic advances might be facilitated were more known about the causes of back pain and the underlying tissue processes.

There is a body of evidence suggesting that degeneration of the IVD underlies a significant proportion of cases of debilitating back pain. This has triggered a new interest in the biology of IVD degeneration. It is too soon to see the clinical translation of much of this new knowledge into clinical practice, but the advances in understanding that have been made in the last few years are already driving a body of research directed towards preventing, halting or reversing the processes of disc degeneration.

Arguably, the two main foci of this work are in restoring the normal environment of the IVD and in regenerating functional IVD tissue. In the former, the major targets are the altered load consequent upon disturbed matrix composition and the abnormal cytokine environment of the degenerate IVD. These have given rise to research on delivery of cytokine modulators to the degenerate IVD [98, 39], novel biomaterials to replace the function of the NP [99, 100] and the use of stem cells to replace deficient IVD cells [101–103]. Reliable new treatments for discogenic back pain based on this new knowledge are a long way off, but the tide of translational research is running in that direction. There are also new research areas developing particularly around mechanotransduction and prevention of degeneration based on recognizing genetically programmed ‘at risk’ groups.

One area that has been neglected to some extent is in the clinical subtyping of patients to identify those who might benefit from the new therapies. Advance in this area will be essential if the new therapeutics are to be of any value, and will go wider than the history and clinical examination but will also encompass clinical technologies such as novel imaging and the wealth of different ‘omics’.

This is an exciting time to be working on back pain and there is little doubt that the clinical management of the patient with discogenic back pain and/or IVD degeneration will be distinctly different in 10 yrs time.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
References
 
The author would like to acknowledge the support of MRC, BBSRC, EPSRC, ARC, Backcare and the Wellcome Trust who have all funded elements of the work quoted here from his laboratory.

Disclosure statement: The author has declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 The normal IVD
 'Degeneration' of the IVD
 New advances in understanding...
 Nerve ingrowth
 Clinical...
 Acknowledgements
 References
 

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Submitted 14 July 2008; revised version accepted 10 September 2008.
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