Back to basics
Published on 01 July 2008
In the first of a new series of features profiling Arthritis Research UK-funded centres carrying out basic science, Arthritis Today reports from Cardiff University School of Medicine.
Professors Charlie Archer and Bruce Caterson with Dr Clare Hughes (seated)
Cardiff University is internationally recognised as one of the UK’s top tier research-intensive universities, and is a member of the prestigious Russell Group of Universities, a status reflecting its culture of research excellence. In 2004, the university underwent a strategic merger with the nearby University Hospital of Wales to create a unified organisation offering new interdisciplinary opportunities and research capabilities. Within this academic hub, two thriving research departments are engaged in intensive programmes of basic science research to address the challenges of musculoskeletal tissue disease.
Set in the beautiful Cathays Park area of the city, the School of Biosciences boasts an impressive platform of research facilities and its current multi-million pound refurbishment programme will make it one of the best equipped bioresearch centres in the world. The Connective Tissue Biology group, one of the School’s six major research areas, headed by Professor Charlie Archer, has a particular research focus on the biology of synovial joint tissues and how these interact in the development of degenerative joint diseases.
Stem cell breakthrough
Once cartilage has been damaged, it is not easily repaired by the body. In younger patients who have suffered mechanical trauma, cartilage can be harvested from neighbouring healthy cartilage and transplanted into the damaged area, but cell regeneration is limited. However, stem cell technology offers new therapeutic potential for cartilage repair. Stem cells have the ability to develop into other cell types, and researchers at Cardiff have identified one type of stem cell taken from human cartilage that has the ability to develop into human chondrocytes (the cells that make up the body’s cartilage) in culture. Professor Archer first established cell types with the characteristics needed for cells to develop appropriately and repair cartilage lesions in animal models. The breakthrough came when the team, funded by Arthritis Research UK and the Swiss AO Foundation, established a similar cell type in human tissue. “We have identified a cell, which, when grown in the lab, can produce enough of a person’s own cartilage to effectively transplant it and make treatment a realistic possibility,” says Professor Archer. “By culturing cartilage from a person’s resident stem cells, we can overcome the limitations of trying to transplant existing cartilage cells. If this research translates into treatment reality, there will be real benefits for patients, particularly those in the earlier disease stages who have not progressed to full-scale osteoarthritis.” The research has progressed sufficiently to embark on initial trials and if the results are positive, clinical trials will follow quickly.
Other research is investigating how mechanical load affects molecular elements of the cytoskeleton (the internal biochemical structure of the cell). Emma Blain, a senior post-doctoral scientist working in Professor Victor Duance’s team, has been Arthritis Reseaech UK-funded over a six-year period and last year was awarded the prestigious British Society of Matrix Biology Investigator’s Award for her work. She explains: “We are modelling the effects of mechanical strain on cartilage cells and looking at the biochemical changes that occur in the cell environment as a result. We have found that compared to healthy tissue, different elements of the cytoskeleton are affected in osteoarthritis tissue.” The outcomes of this research could have important implications for the management of cartilage damage, and may be significant for studying the ffects of exercise and obesity on cartilage structure. The School of Medicine’s Department of Medical Biochemistry and Immunology is a large and dynamic research-dominated centre with many interlinked research strengths. It hosts a range of high profile research groups concentrating on cartilage biochemistry, inflammatory disease, and immune cell functioning. A combination of basic science and applied clinical studies encourages a translational research approach, driving new developments from bench to bedside.
New hopes for osteoarthritis therapies
Osteoarthritis (OA) affects some two million people in the UK and yet, despite its prevalence, remains a difficult disease to treat. Alongside his fellow professors, Professor Bruce Caterson heads up a large Arthritis Research UK-funded programme of osteoarthritis research. He points out: “Despite the slow progress in therapeutic advances for osteoarthritis, it has become increasingly clear that synovitis, the inflammation of the joint lining, plays an important role in the progression of the disease. In rheumatoid arthritis, inflammatory cells called macrophages are known to be the main promoters of disease activity. They produce, and stimulate the production of, a range of degradative chemicals that are essential in ’normal’ inflammation, but are harmful when overproduced. But in osteoarthritis, much less is known about the detail of these inflammation processes and this is our focus of interest.”
A unique enzyme in osteoarthritis
Dr Clare Hughes, an Arthritis Research UK-funded senior lecturer, is studying how enzymes are involved in cartilage breakdown (enzymes are biomolecules that speed up chemical reactions). The key structural component of cartilage, a substance called aggrecan, is a protein material that is destroyed very early on in the disease process. The enzymes that attack aggrecan are called aggrecanases – they chop the protein up into sections ready for further degradation and generally speed up the whole breakdown process significantly. Dr Hughes has discovered a new form of one aggrecanase which has a different molecular structure. It is found in the synovial capsule of the joint and she is working to establish which type of joint cell produces it, how it functions, and how it can be measured easily so that its potential as a diagnostic or therapeutic agent can be assessed. “This enzyme is very interesting because, to date, it has only been found in human tissue, and only in osteoarthritic conditions, suggesting it may be particularly relevant to the control of osteoarthritis,” comments Dr Hughes. “Potentially it could be used as a diagnostic test for the condition, or utilised to develop an inhibitory therapy.”
Novel therapies for rheumatoid arthritis
Dr Mari Nowell and Dr Simon Jones
Dr Simon Jones is funded by a 3-year Arthritis Research UK project grant to investigate a key inflammation mediator, know as interleukin (IL)-6. Production of this molecule is increased significantly during inflammation and it normally acts to promote the inflammatory response, helping to prevent infection spreading and clearing up damaged tissue. However, when the control mechanism breaks down, it causes overproduction of damaging biological agents, which then destroy healthy tissue. IL-6 has already been extensively studied and drugs to block its actions have been developed with some clinical success. But, as Simon Jones points out: “It is difficult to judge whether a complete blockade of IL-6 will not give rise to clinical complications. The control of IL-6 is highly sophisticated and we are currently exploring the possibility of selectively blocking aspects of IL-6 activity that may be damaging in arthritis.”
His studies have revealed a crucial difference in the way that IL-6 interacts with joint tissue cells and the way that it interacts with other body cells, such as immune system cells. By exploiting this difference, he has developed jointly with a group in Germany a therapeutic approach to blocking IL-6 activity in joint cells only.
He explains: “In joint tissue, if we administer a soluble agent, called soluble gp130 (sgp130), it selectively blocks certain activities associated with IL-6. sgp130 occurs naturally in the body but we have produced it in quantity in the lab and tested it on animal models. When it’s given in arthritic conditions, no further joint damage occurs,”Dr Jones points out: “Its action is remarkable and is capable of reducing joint inflammatory and joint disease progression. In addition, sgp130 doesn't appear to interfere with immune cell function around the body. Its therapeutic potential is therefore considerable.”
The research has progressed sufficiently to begin considering clinical trials, and Simon Jones and his team intend to seek further support from Arthritis Research UK to take their research forward.
Dr Mari Nowell, a research associate in the department, has been investigating joint biochemistry for several years and is enthusiastically developing her own research niche supported by a five-year Arthritis Research UK non-clinical career development fellowship. Currently, she is studying a novel inflammatory mediator, known as PBEF, which causes tissue damage in rheumatoid arthritis (RA). Dr Nowell is interested in this particular mediator because its concentration is high in the synovial fluid of rheumatoid arthritis patients and it is activated during arthritic episodes. Levels of PBEF correlate directly with other common rheumatoid arthritis measurement indices such as rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and DAS28 scores, and levels of this protein are a good indicator of disease state.
Earlier studies determined that PBEF is produced by cells in the joint tissue and released into the joint environment where it stimulates the production of tissue destroying chemicals. Like IL-6, when too much of it is produced inflammation persists and joint degeneration occurs. Why this happens in some people and not in others is very much under the control of genetics.
In collaboration with Dr. Rachelle Donne at the functional genomic group at the Arthritis Research UK epidemiology unit in Manchester, Dr. Nowell hopes to investigate genetic variations that may predispose individuals to PBEF overproduction."
This approach may help to identify which individuals are most likely to benefit from treatment, and may also explain how PBEF production is switched on and off.
Having tested an anti-PBEF agent in animal models of arthritis and established that it inhibits disease progression, she is currently testing out different dose regimens to find out how effective the agent is when given at different stages of disease progression. Although the work is still in the early stages, the results are very promising.
“If anti-PBEF factor is effective in the early stages of arthritis, it could possibly halt disease progress before too much irreversible damage occurs at the cartilage level,” says Mari Nowell. “The current strategy for rheumatoid arthritis treatment is to use an anti-TNF combined with methotrexate; drugs that use completely different biochemical pathways to exert their effects. It may be that a cocktail of the latest biological drugs, including new therapies such as anti-PBEF, could have additive effects and result in an even more beneficial treatment.”