• Progress To Date (January 2006)
  
  Funding for EURODISC has now come to an end. Blood samples, disc tissue and clinical details were collected from nearly 600 backpain patients throughout Europe. The disc tissue was used for histological grading and cell biology assays. DNA from the blood samples was genotyped and used to look for gene polymorphisms associated with disc degeneration. A number of statistically significant correlations between genotype and phenotype were found and progress was made in other areas, as follows:-
  
  Disc pathology
  
  SNPs.
  A number of significant correlations between SNPs and disc disorders were established. These associations obviously require further investigation both to confirm these findings on other population samples and to investigate mechanisms and interactions with environmental and behavioural factors.
  
  In agreement with a number of other studies, collagen IX polymorphisms were associated with herniation and also with pain, as were polymorphisms of collagen XI, collagen III and aggrecan. Surprisingly, the results showed no significant association between degeneration and polymorphisms of the VDR receptors possibly because of the difference in sample populations between our study (predominantly British and German) and those of previous reports (Finnish) pointing out the necessity of investigating different European population groups in such studies.
  
  A new finding was the association between MMP8 polymorphisms and spinal stenosis and spondolysthesis; this again requires confirmation, but if it is predictive it might target a population where spinal stenosis, a common cause of disability in the elderly, could be prevented by treating disc degeneration at an early stage. Polymorphisms of MMP9 were predictive for recurrence of herniation, again a finding which could be useful clinically if confirmed.
  
  Clinical and Environmental Correlations.
  Correlations were seen between painful disc herniation and job strain and painful disc herniation and smoking. Smoking was also associated with increase in disability as measured by the ODI. These correlations are in agreement with other findings. No other environmental factors appeared to be related to disc degeneration or pain.
  
  Experimental findings
  Studies from several partners showed the importance of the mechanical environment in determining disc cell and tissue behaviour. There were large person-person variations in response to the same mechanical signal. No correlation with any of the SNPs examined were seen; differential responses could either arise from SNPs in signalling or receptor molecules which have not been identified to date or from cellular adaptations to varying degenerate conditions. Dr Neidlinger-Wilke will continue to examine this relationship in a new project financed by the German Research Council. Combinations of mechanical modelling and confocal microscopic observation have been used to estimate changes in the pericellular environment in mechanically stressed disc in order to further elucidate mechanical signalling. Mechanical signals appear to be a regulator for neural and blood vessel ingrowth; a new finding was that they stimulate production of pleiotrophin, an angiogenic molecule, by disc cells.
  
  Effect of degeneration on tissues and cells was examined in a number of different ways. Cells from herniated discs were found to show premature senescent changes indicating that they are unsuitable for use in biological repair therapies. This premature ageing was observed by serial subcultures of cells; cells from bovine discs have a significantly extended lifespan (up to 120 passages) compared to cells from degenerate human discs (25 passages). As far as the tissue was concerned, turnover times of matrix macromolecules in the disc were found to be very long, over 100 years for collagen and 25 years for proteoglycans; increased rates in degenerate discs indicate that repair processes can be initiated. However fall in swelling pressure with increase in degeneration and ageing suggests that this process is not successful to any great extent. No correlation was seen between MRI degenerative findings using standard clinical criteria and nutrient transport coefficients, indicating that MRI diagnosis cannot provide this important diagnostic information.
  
  Pathogenesis of disc degeneration.
  
  Significant results from this project in relation to pathogenesis indicate the importance of nutrient supply to the disc in development of disc degeneration, slow turnover times of aggrecan indicating that this major macromolecular constituent is not replaced rapidly, and the finding that there is significant senescence evident in discs from surgical patients. All these findings indicate that biological repair of the disc will be difficult as there is no obvious source of cells for implantation, cells may not survive through lack of nutrients even if implanted, and if they survive, restoration of the disc matrix will be slow (years rather than weeks or months).
  
  Biology
  
  A three-dimensional finite deformation swelling model of the disc, equipped with a fiber architecture as histologically observed in the human intervertebral disc, has been used to predict time-dependent responses of discs to mechanical loading. Solutions of the model predict the stress peaks seen in degenerate and aged discs consequent on loss of proteoglycan and hydration and validate its predictive capacity. A finite element model for calculating nutrient gradients through the disc has been developed in collaboration with Prof Shirazi-Adl in Montreal, using substrate-and pH dependent rates of lactate production and oxygen consumption; the model shows the importance of taking account of such interactions in modelling nutrient and metabolite gradients. It also shows that there is a critical value of nutrient exchange area below which nutrient levels in the disc centre fall very steeply.
  
  We have applied different mechanical stimuli (cyclic strain and hydrostatic pressure) to human and bovine disc cells in vitro to analyse the effects of mechanical stimuli on gene expression. The effect of the osmotic environment was studied to simulate the diurnal change in hydration and hence osmolarity of the disc; cellular responses were very sensitive to the osmotic environment and mechanical signals which stimulated gene expression under one osmolarity could inhibit it under other osmotic conditions. Results indicate a large person-person variation in response with cells from some patients being highly responsive to mechanical stress whereas others were nonresponders.
  
  We found that angiogenesis and neural ingrowth were stimulated by mechanical signals. Further investigation indicated that mechanical stress upregulated pleotrophin expression; possibly expression of other angiogenic and neurotrophic factors are also influenced by mechanical stress. Measurement using several different techniques found that cells from herniated and degenerate discs show senescent changes and also have a reduced proliferative lifespan indicating that these cells are not suitable for use in cell based therapies despite the current clinical practice and that their use should be avoided.
  
  Diagnosis
  
  The results of this interdisciplinary approach to investigating disc degeneration indicate that current diagnostic techniques are not able to identify many features associated with the pathogenesis of disc degeneration such as cell senescence and cell death or loss of nutrient pathway. Development of predictive diagnostic techniques on patients screened for disc degeneration associated polymorphisms, could lead to improved preventative and treatment interventions.
  
  Further Reading:
  
  More details of the EURODISC study
  EURODISC publications Back to top