Current Research

Cellular Senescence in Degeneration of the Intervertebral disc

Click here to view more information (PDF)

Dr Judith A Hoyland, Tissue Injury and Repair, School of Medicine, The University of Manchester.

Ageing and degeneration of the intervertebral disc (IVD) is poorly understood. This is reflected in current treatment for the associated low back pain which is either symptomatic, or seeks to remove small parts of the disc or replace the damaged disc with bone (fusion) or an artificial disc, both of which are unsuccessful approaches in the long term. We believe that if there were more known about the cellular processes of ageing and degeneration of the IVD novel therapies could be designed to target the underlying processes themselves. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesise that this is due to accelerated cellular senescence (cells aging faster than expected) which causes fundamental changes in the ability of disc cells to maintain the IVD matrix thus leading to IVD degeneration and the associated back pain. To date our work, funded by DISCS, has shown that cell senescence occurs in vivo in the IVD and importantly appears to be accelerated in disc degeneration. Furthermore the senescent cell phenotype (observable characteristic) is associated with altered cell behaviour leading to the features that characterise disc degeneration (e.g. decreased matrix synthesis and increased matrix degradation/breakdown). We have shown that the senescence in IVD degeneration is probably due to stress induced senescence brought about by the up-regulation of a molecule known as caveolin -1.

Future work is concentrating on which factors may up-regulate caveolin expression in the IVD and initial experiments will focus on the cytokine interleukin 1 (IL-1) which we have previously shown to be increased in IVD degeneration.

From our current understanding of the behaviour, biology, viability and life span of senescent cells this study could have significance in the following areas:

i) At a basic scientific level to advance our understanding of the processes leading to disc degeneration;

ii) In identifying potential new targets for intervening in the development of disc degeneration particularly the “stress events” leading to stress induced senescence; and

iii) In the design of new treatments for IVD degeneration, such as tissue engineering/regeneration, in which the plan is to stimulate existing native disc cells to manufacture new matrix or to use autologous IVD cells to populate biomatrices.

Update – December 07

Over the last 3 months we have investigated which factors may up-regulate the expression of the molecule caveolin -1.   Initial experiments have focused on the cytokine interleukin 1 (IL-1) which we have previously shown to be increased in IVD degeneration and the effect of nutrient deprivation (availability of nutrients in the degenerate IVD is poor). Isolated intervertebral disc cells in the laboratory have been subjected to conditions of low serum (to mimic poor nutrition seen in the IVD), or treated with IL-1, to ascertain whether these factors can induce cellular senescence.   Preliminary results suggest that low serum in the culture medium induces a senescence which indicates that poor nutrition in the disc may cause cell abnormalities leading to the tissue changes seen in the degenerate IVD.  Experiments with IL-1 are currently ongoing.

The abstracts submitted to the American Orthopaedic Research Society [conference March 08] and the World Forum for Spine Research [conference January 08]  have both been accepted for poster presentations.

Update – April 08

our work has shown that there is increased cellular senescence in degenerate intervertebral discs which is not linked to increasing age. It suggests that stress induced premature senescence is occurring to accelerate the process involved in discs degeneration.

Since February 2008 through collaborations with the Tissue Services at the National Blood Service, and with ethics approval, isolated intervertebral discs cells from human discs have been subjected to conditions of low serum to mimic poor nutrition in the IVD, or treated with IL-1 to ascertain whether these factors can induce the senescent phenotype. Preliminary results suggest that low serum in the culture medium induces a senescent phenotype and we are currently optimising the conditions for IL-1 stimulation

Investigation into muscle fat and its affect on back pain

Research being carried out by Alison McGregor PhD, MSc, MSCP, Reader in Biodynamics at Imperial College London.

Lower back pain is a common, disabling, expensive and often chronic problem. Our understanding of how the spine works is limited, and consequently it is difficult to identify which part of the lumbar spine contribute to the development of low back pain. It also makes advice about protection of the back inadequate.

Increasingly the role of the spinal muscles in protecting the back has been highlighted, while impairments in the strength of these muscles have been noted in people with lower back pain. MRI scans indicate there is a high fat content in the muscles of people with back pain. Something that is not normally seen in healthy muscles. We have been exploring the muscles in patients having surgery for back and leg pain. This research is on-going but to date we have seen important changes in the muscle structure and content

Update December 07

The project is progressing and we have the final patients enrolled, with a total of 8 enrolled (although one withdrew from surgery) and there are a further 2 booked for scans and surgery either later this month or next month. Once we have this final data we will review our findings and see if there is sufficient information to progress to a larger clinical study.

Understanding spinal injury mechanisms

Research led by Alison McGregor PhD, MSc, MSCP, Reader in Biodynamics at Imperial College London.

Low back pain and injury is a common problem amongst rowers. Our on-going studies have been trying to identify the mechanisms of injuries including studies to measure the motion of the back during rowing under a variety of work load conditions using a range of athletic skills from novice to elite. Our current project is developing the instrumentation on a rowing ergometer so we can understand the movements of the back as well as the forces being generated by the body. Through a mathematical model we hope to use this information to determine the loads being generated within the back. To date we have instrumented the handle and more recently the seat of the ergometer and are currently working on a robust system to look at the force generated at the feet. The image below gives an example of the force pattern generated at the seat during a single rowing stroke. This will be integrated with information on how the rower is moving.

Update December 07

The project is progressing, the last piece of instrumentation has almost been completed and we hope to integrate it with the rest of the system in the next few weeks, the associated modelling is progressing and we continue to test our GB rowing team athletes.

The impact of surgery to relieve leg pain on cortical control of trunk and leg muscles

Research led by Paul Strutton PhD, Principle’s Lecturer in Anatomy & Alison McGregor PhD, MSc, MSCP, Reader in Biodynamics at Imperial College London.

Low back pain is an enormous problem in western society with social and financial costs high and still increasing. There are many studies which have implicated changes in the muscular stabilising system surrounding the spine as contributory to the formation of low back pain. Our studies have revealed that, in patients with chronic low back pain, there are changes in the pathways controlling movements from the brain to some of these muscles. However, it remains to be established if these changes contribute to, or are an adaptive change to the low back pain.
Surgery to relieve symptoms of back and leg pain is often undertaken when more conservative treatment options have had limited success. However, poor functional outcome and patient satisfaction and the return of symptoms in many cases warrant further investigation. It is not clear whether the changes within the brain pathways to the muscles that we have observed in chronic back and sciatica pain patients yet to undergo surgery can be reversed by such surgical intervention and whether those patients who recover best have the greatest changes in these pathways following the surgery. We anticipate that this work will provide novel insights into the time course of the changes occurring at the level of the central nervous system and furthermore which of these changes are reversed by surgery.

Update December 07

This neurophysiology PhD project is going well and the researcher now has the protocols in place and is actively recruiting patients into the study.