The Cellular Pathobiology of the Degenerate Intervertebral Disc and Discogenic Back Pain

A. J. Freemont

Disclosures

Rheumatology. 2009;48(1):5-10. 

In This Article

New Advances in Understanding the Altered Cell Biology of Ivd Degeneration

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-1α 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.[20,29,30,31,32]

  • 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.[38,39,40]

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,[42,43,44] 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-α. 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-α applied to nerve roots caused vascular and radicular abnormalities similar to those seen following application of NP tissue,[47] implicating TNF-α in nerve root damage and sciatic pain. Furthermore, application of TNF-α blockers[48] prevented the processes and symptoms. It was therefore hypothesized that TNF-α 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-α in back pain comes from a recent study in the TNF-α-deficient mouse which has provided evidence that TNF-α 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-α 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 α1,[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.

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