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For more information, go to www.arthritisresearchuk.org

Back to basics: Sheffield University

Published on 01 October 2009
Source: Arthritis Today

Professors Peter Croucher and Richard Eastell with Vice Chancellor Professor Keith Burnett and Professors Jack Martin and Graham Russell at the opening of the Mellanby Centre

The opening of a new bone research centre at Sheffield University has signalled an intention for more collaborative work, and to consolidate already close links with Arthritis Research UK.

When it comes to osteoporosis research, there are only three centres in the world rated higher than Sheffield University – the University of California, Harvard and Yale in the US – so it’s in exalted company.

Sheffield is unusual in that its clinical research spans bone diseases from the very young to the very old, encompassing not just osteoporosis but also the childhood form of brittle bone disease osteogenesis imperfect and bone cancers.

Its clinical research, widely supported by Arthritis Research UK in recent years, is underpinned by a basic biomedical research, which has now been brought together in a single unit and involving five departments within the medical school. The Mellanby Centre was opened earlier this year by two former alumni of the university renowned for their glittering careers in bone biology research UKh, Professors Jack Martin and Graham Russell.

While the Mellanby Centre, with its labs and high-tech equipment, will concentrate very much on basic science, Professor Croucher, joint centre director with Professor Richard Eastell, stresses that they want to develop new approaches to treating bone diseases, and to translate research discoveries via the new National Institute for Health Research-funded Biomedical Research Unit for Bone at the Northern General Hospital in the north of the city.

"Two of our main aims are to translate advances in research into benefits for patients, and to promote the profile of skeletal research in the UK," he says.

"There are many good groups of people working in many universities, but the advantage of bringing them together under one roof where they can talk to each other and share ideas.

"We want to bring together a lot of people with interests not just in arthritis and bone disease, but also in children’s bone diseases and bone cancers, and to try and learn the lesson from one disease and apply it to another. Sheffield is very strong on the bone cancer side and there are things we are doing in cancer research that can be applied to osteoporosis and osteoarthritis – there is a lot of potential for cross fertilization, and we would hope that would be of interest to Arthritis Research UK in the future."

Doctor Alison Gartland

Three researchers at the medical school are already receiving funding from Arthritis Research UK in pursuing very different research agenda. Dr Alison Gartland, lecturer in bone biology, is now based at the Mellanby Centre, and has a new project grant to investigate bone and cartilage loss in inflammatory arthritis.


Special molecules in joints

Currently, rheumatoid arthritis therapies designed to combat inflammation in rheumatoid arthritis aren't always effective in all patients and can have serious side-effects. These drugs typically block the inflammatory chemicals that destroy joint tissue but at the same time also shut off the body's ability to fight infection. New targets and treatments are needed that utilise a more subtle approach to the problem and understanding the detail of the molecular mechanisms involved in inflammation should help to achieve this.

Dr Gartland explains: "We're looking at a receptor called P2X7 that's just one of hundreds of receptors present on the surface of cells all over the body. It's present on bone and cartilage cells and may be important in regulating the joint tissue destruction that occurs in rheumatoid arthritis (RA).

Receptors are special responsive areas that can be activated by chemical signals. Once activated, the cell starts to produce molecules that affect the way the surrounding tissue works. It's a bit like pressing a button and switching on a production line inside the cell. In the case of P2X7, we know that it's involved in inflammation but we don't know what it does to the actual cartilage in a joint. We're investigating how this receptor works in healthy joints so that we know what aspects of its activity are important for normal function."

Genetic differences affect bone loss

The P2X7 receptor also exists in different forms, or "polymorphisms", depending on its genetic make-up. Dr Gartland and co-workers have found that in women with the normal fully functioning P2X7, bone loss is less severe than in women with the polymorphic receptors.

"This suggests that the severity of disease may be linked to the polymorphisms," she says. "If patients with polymorphisms experience more severe bone loss, we could screen for this genetic difference. Individuals who are positive for these polymorphisms could then be given treatments to prevent or slow bone loss at a much earlier stage, before irreversible damage has occurred."

The test would be part of a profile of prognostic tests to help assess risk of disease development. Therapies are already available to inhibit these receptors and this test may be useful to predict which patients will and won't respond well to therapy, and direct treatment accordingly.

As well as aiding prognosis and disease management strategies, the results of this research should benefit other musculoskeletal diseases such as osteoporosis and osteoarthritis.

Epigenetics: a new approach to disease management

The development of anti-TNF drugs represents a considerable breakthrough in terms of arthritis therapy. Tumour necrosis factor, or TNF, is an inflammatory chemical that's normally produced to protect the healthy body against infection. However, in rheumatoid arthritis, TNF production is continuous, and chronic pain, swelling, and eventually joint damage results.

Professor Gerry Wilson, head of academic rheumatology in the School of Medicine and Biomedical Sciences, is investigating how 'epigenetics' influences TNF production.

Switching genes on and off

Epigenetics (meaning "over" or "above" genetics) is a rapidly advancing area of research that is changing the way we understand disease processes. We may be born with a set of genes that programme our bodies but the activity of these genes is influenced by epigenetic factors.

These factors often work as simple on/off switch mechanisms: all our cells carry the same genes but only specific ones are "active" or expressed where they are needed. Pancreatic cells, for example, produce insulin but kidney cells don't. The insulin producing genes are switched on in the pancreas but switched off in the kidney.

Professor Wilson comments: "Epigenetics play an important role in the development of human disease, including arthritis and cancer. In rheumatoid arthritis it may influence how severe the disease is and how patients respond to treatment. But the system is very complex – there are hundreds of thousands of epigenetic variations that switch genes on and off in different combinations. If we can find out how epigenetics affects the production of chemicals like TNF we might be able to devise new therapies to regulate this, and dampen down the aggressive nature of the disease."

Predicting disease risk

Epigenetic markers can be measured and by comparing them in healthy individuals and individuals with rheumatoid arthritis, the ones responsible for different effects, like the overproduction of inflammatory chemicals, can be identified.

"We've already found a small difference in one of these markers that is linked to the production of IL-6, a major inflammatory molecule," says Professor Wilson, "and increased epigenetic markers are associated with higher TNF production."

The epigenetic marks on the TNF gene change with age as does the risk of developing rheumatoid arthritis. Could this marker be a predictor for rheumatoid arthritis risk or severity? If so, this could be a very useful clinical test to help disease prognosis, guide treatment, and predict treatment outcomes.

A ‘virtual tendon’

Tendons are tough, flexible pieces of tissue that attach muscle to joints and convert muscle force into skeletal movement. Damaged tendons lose their stretch and flexibility, causing considerable pain and immobility. The healing process is difficult and lengthy because the underlying tendon fibres don't always repair properly and patient quality of life is reduced.

Research aimed at improving tendon repair is difficult because studies rely on cell cultures grown in laboratory conditions and these don't model the real life situation very well. However, a revolutionary new research tool is about to change the way that we view tendon repair.

Dr Dawn Walker, Research Councils UK Fellow and lecturer in the Department of Computer Science, is attempting to create a "virtual tendon" using sophisticated computer simulation technology, with funding from an Arthritis Research UK project grant.

Computer simulation – a valuable model

Dr Walker, a physicist by training, has extensive experience in the application of computer simulation technology to living tissue systems. She has successfully developed models for other tissue types and will adapt some of the software from these projects for use in the current project.

"Tendon isn't the most popular tissue to research" she says. "In the media, the heart or brain are much more interesting areas of development. The "virtual heart" project hit the headlines some years ago and is now proving to be an extremely valuable model for cardiac research projects. However, tendon problems are very common and cause immense suffering - we really need to address this disease area and improve predictive outcomes and treatment methods."

Modelling tendon damage

The project combines established knowledge of tendon structure and tissue dynamics with information from current laboratory research projects studying the effects of damage and repair in living tendon cells.

"All the data is integrated into the programme", says Dr Walker. "We know how tendon is constructed in healthy tissue and what happens to it when it's subjected to the stresses and strains of exercise, overwork and injury. It's important that we develop the model by testing it at every stage against real laboratory data to be sure that our model mimics the real life situation and is relevant to patient outcomes."

Once the model is up and running, any combination of parameters can be altered to represent different patient types and tissue damage, and the outcomes assessed. Eventually, the project aims to use the virtual tendon to inform therapy options and assess outcomes.

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