Back to basics
Published on 01 October 2008
Arthritis Research UK is currently investing almost £2m on promising research into osteoarthritis and soft tissue disorders at the Biomedical Research Centre, University of East Anglia.
There is little doubt that drug developments, such as anti-TNF therapy, are revolutionising approaches to the management of arthritis. But for some forms of this disease, such as osteoarthritis (OA) and soft tissue problems, the drug development pipeline seems slow-moving in comparison. So it’s encouraging to know that ground-breaking research currently underway at the University of East Anglia (UEA) is successfully unravelling some of the complex biochemistry that regulates these disorders – knowledge that could have a major impact on future therapeutic choices in the not so distant future.
The recently completed Biomedical Research Centre (BMRC) at UEA is a unique collaboration between UEA’s acclaimed School of Biological Sciences and the School of Medicine, Health Policy and Practice – one of Britain’s first new medical schools for almost 30 years when it opened in 2003. Within this purpose-built research base, pioneering work into a range of health and disease areas, including arthritis and other musculoskeletal disorders, is establishing new perspectives on some of medicine’s toughest dilemmas. Strong links with clinical colleagues in musculoskeletal medicine (Professors David Scott and Alex MacGregor, Mr Simon Donell and Mr Adrian Chojnowski) keep the patient perspective clear.
Enzymes in osteoarthritis - not just ‘wear and tear‘?
Ian Clark, a former Arthritis Research UK fellow and recently appointed to a new Professorship, is utilising advanced molecular biology techniques to investigate cartilage destruction in osteoarthritis (OA).
“Cartilage damage is debilitating and largely irreversible,” points out Professor Clark. “And trying to halt or prevent this damage is an ongoing challenge for medical research. We know that cartilage breakdown is poorly understood in OA , a condition that has misleadingly been written off as just an inevitable disease of the elderly, caused by ‘wear and tear’. By identifying and understanding the actions of some of the key molecules underpinning this breakdown process, we aim to target potential therapy options.”
The key molecules under investigation here are enzymes – substances which speed up the rate of chemical reactions. In the human body, much of our tissue has a protein structure and the enzymes that break this down are called proteinases, or proteases. There are more than five hundred different proteases throughout the human body, and they act like biological scissors, chopping up large protein molecules into small pieces ready for further degradation. In healthy tissue, enzyme action takes care of normal tissue turnover, but in disease states, excessive enzyme activity causes tissue destruction.
Professor Clark has a wealth of experience researching the control of enzyme function in tissue metabolism. He is justifiably proud of the protease research capacity at the BMRC, which boasts a collaborative working environment combining an impressive resource of skills and knowledge in a variety of human diseases. “We share extensive facilities and experience across a multidisciplinary platform of protease projects,” he comments, “and this creates an excellent working environment in which everyone benefits.”
One project is looking at the normal pattern of enzyme production in healthy tissue and comparing this with the pattern of enzyme production in OA. The difference between the two patterns should indicate what enzyme changes occur during cartilage destruction.
Analysing large numbers of normal and OA tissue samples
Professor Clark comments: “We have technology which allows us to measure the levels of all the relevant enzymes in cartilage. We need to analyse large numbers of normal and OA tissue samples from patients, and sourcing good quality samples for research purposes can be problematic. Fortunately, we have an extremely close link with the Department of Orthopaedics at the Norfolk and Norwich University Hospital where academic consultant orthopaedic surgeon Simon Donell helps us obtain valuable surgical samples. We use samples from two consenting patient groups undergoing hip replacement surgery, OA patients for disease tissue samples and fracture patients for normal tissue samples.”
The analytical capacity is impressive: 560 proteases have been analysed in the two tissue types, and the study has generated some exciting new information. Two new enzymes have been discovered at much higher levels in the OA samples than the normals. These two enzymes (called MMP-28 and ADAMTS-16) have never previously been investigated or described in cartilage, and so their presence in OA is an interesting and potentially very significant discovery in this difficult to treat disease.
The new research has been boosted by a recently awarded Arthritis Research UK grant and will benefit from collaborative work with Professor Chris Overall and colleagues in Vancouver, Canada, renowned for their expertise in high throughput protease technology.
Adds Professor Clark: “Our current research is focusing on the biochemistry of these enzymes, the regulation of their gene control in joint cells, and their role in cartilage metabolism. This detail is crucial to the successful development of a future therapy. We need to be sure that we are developing a treatment that doesn’t interfere with other reactions in the body, and one that has minimal side effects. If we can inhibit these enzymes, we may be well on the way to preventing uncontrolled cartilage loss in OA.”
Tendon trouble - an enzyme investigation
Soft tissue problems are the third most common type of arthritis disorder but are difficult to treat because so little is understood about their underlying pathology. The tendon is the major site of soft tissue problems, and tendinopathy – or tendon injury – occurs not only in the middle-aged to elderly population, but also in the sporting and physically active younger generations. Although these injuries account for about 30 per cent of all GP consultations for musculoskeletal problems and constitute 39 per cent of all new patients seen in rheumatology clinics, treatment approaches vary enormously.
At UEA, a research programme under the leadership of Dr Graham Riley is investigating tendon malfunction with the aim of providing new knowledge to help clinicians with treatment and prevention. Dr Riley holds an impressive international reputation for his extensive experience and expertise in this area of research. Formerly Head of the Soft Tissue Injury and Repair Group at Addenbrooke’s Hospital, Cambridge, where Arthritis Research UK project grants supported his preliminary studies into tendon degeneration, Dr Riley has recently been awarded a five-year arc senior research fellowship of more than £500,000 to support further research.
Dr Riley explains: “Put simply, tendons are the fibrous tissues that connect our muscles to our bones and are absolutely essential for normal movement. They are strong, rope-like structures that can withstand tremendous strain but, like any material under constant and repeated use, can suffer stress damage and become injured and non-functional as a result.”
Many individuals get little relief from treatment
Tendinopathies may be long-term conditions or acute tissue ruptures, caused by repetitive tendon ‘overuse’, or by sudden exertion, respectively. Surprisingly, a significant proportion of cases also occur in individuals with relatively inactive or sedentary lifestyles. Degenerative tendinopathy is a chronically persistent condition that causes severe pain and immobility, and accounts for many millions of pounds in lost employment and medical costs annually. Many individuals get little relief from treatment and often have to accept that their joint problem will never get better. They may have to stop work and give up hobbies and activities.
“When loss of tendon function occurs,” says Dr Riley, “it can be very difficult to reverse the condition, and this emphasises the need for early and effective recognition and treatment. Unfortunately, conventional therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), steroid injections, and physiotherapy, have only limited success, and there is a pressing need for new therapeutic approaches to be established.”
Excessive enzyme activity causes the tissue structures to weaken
Just like the OA cartilage degeneration story, tendon disease is associated with abnormal enzyme activity, although different enzymes are involved here. Excessive enzyme activity causes the tissue structure to weaken, making it more prone to micro-tears and rupture. “We needed to identify which enzymes cause this damage and how they function,” says Dr Riley. “Ultimately, our research goal is to find a method of modifying enzyme function that will halt damage, and achieve tissue repair or the resolution of symptoms.”
Graham Riley began his research fellowship in Cambridge, sourcing tissue from healthy individuals and tendinopathy patients for comparison. In an approach similar to that of the cartilage work, he has generated and compared the enzyme profiles of the two tissue types, and identified which enzyme levels change significantly in tendon breakdown. The discovery that two enzymes (MMP-23 and ADAM-12) are significantly increased in damaged tissue has led to exciting possibilities for potential therapy developments.
“These enzymes have never been found in tendons before. We’re going to investigate how they work, why they increase in disease, and how they are controlled,” he adds. “If we can understand what regulates the changing pattern of enzyme activity, we may be able to develop targeted drug therapies to block their action and pave the way for new drugs to combat this painful disease.”
Taking the strain – optimising therapy opportunity
Another aspect of the Norwich studies involves the investigation of mechanical strain upon tendon cells. Mechanical strain, i.e. anything from simple movements to strenuous exertion, plays a major role in keeping connective tissues healthy, especially in tendons. Immobilisation, caused by bed rest in disability or illness, for example, causes dramatic deterioration of cartilage and tendon structure. But, whilst some loading is known to be beneficial, overloading or sustained repetitive loading is damaging and known to be a major factor in the development of tendinopathy.
Dr Riley is using a sophisticated model of artificial strain application that mimics natural loading on tendon cells. A range of loads are applied to cells grown in culture and their effects upon cell activity and the production of enzymes are assessed.
The implications for treating tendon injury are significant
"The implications of these research outcomes for treating tendon injury are significant,” says Dr Riley. “It seems likely that there is a window of opportunity for therapy following injury in which irreversible disease progression could be prevented. Physiotherapists and clinicians are asking crucial questions about the treatment of diseased and injured tendons - they need to know the degree of mechanical loading that will be beneficial - and we need to be able to give them assurances from evidence-based research. We hope that these studies will provide at least some of the answers.”