Published Autumn 1998

Osteoarthritis research: targeting its causes and consequences

Reproduced from Issue 102 of Arthritis Today

Osteoarthritis has traditionally taken second place to rheumatoid arthritis in the field of medical research. No longer. Dr Gillian Wallis, of the Wellcome Trust Centre for Cell-Matrix Research in Manchester, explains the latest developments. 

Osteoarthritis is the most common joint disease of man and is the cause of more than 60% of all joint replacements. Because it leads to pain and disability, particularly in the elderly, and with the percentage of elderly people in the UK population rising, osteoarthritis is becoming an increasingly important public health problem.

arc currently funds a repertoire of projects in varying centres within the UK that examine clinical, epidemiological, genetic and biological aspects of osteoarthritis.

Interest in the disorder is now no longer confined to the patient and the medical practitioner, but has captured the interest of researchers, pharmaceutical companies and government organisations. Osteoarthritis is not, however, a single condition but represents a broad spectrum of disorders. The causes of the condition are a combination of genetic and environmental factors. The consequences of the condition may be mild or severe and the pattern of joints involved may differ from one individual to another.

The biological processes that underlie the joint failure are equally complex, involving both degradation and repair of the cartilage overlying the joint and deposition of new bone at the joint surfaces and margins.

Osteoarthritis research reflects the complexity of the condition and arc currently funds a repertoire of projects in varying centres within the UK that examine clinical, epidemiological, genetic and biological aspects of osteoarthritis.

arc-funded osteoarthritis research conducted by Professor Mike Grant, and his multidisciplinary research team at the University of Manchester, aims to identify targets for the development of drugs that may prevent, halt or slow the destructive processes of osteoarthritis.

The identification of such targets is being approached in two ways. First, genetic methods are being used to identify genes that make certain individuals more susceptible to osteoarthritis than others. Second, the biological processes that lead to the deposition of new bone in the osteoarthritic joint are being examined.

The genetic basis of osteoarthritis

Certain forms of osteoarthritis are more common in some families than in others, implying that there is a genetic component to the condition. One form of osteoarthritis that runs strongly in families is generalised nodal osteoarthritis, which leads to the formation of nodes on the finger joints as well as large joint osteoarthritis. In order to discover which genes underlie this condition, a collaborative project involving Mike Doherty (Professor of Rheumatology) at the University of Nottingham, Mike Grant, Gillian Wallis (Lecturer in Medicine) and Bill Ollier (Professor of Immunogenetics) at the University of Manchester in under way. For the purpose of this study, more than 200 families with generalised nodal arthritis have been recruited and their blood samples taken. These samples are being analysed using more than 300 different chromosomal markers to determine where within the human genome the susceptibility genes reside. These samples have revealed at least three potential chromosomal locations for susceptibility genes and these regions are now being investigated further to identify the genetic defects that underlie this form of osteoarthritis. The discovery of the susceptibility genes will provide information about how this disorder develops – information that could be valuable in the development of rational medical strategies aimed at the treatment and prevention of this form of osteoarthritis.

these regions are now being investigated further to identify the genetic defects that underlie this form of osteoarthritis

The biological basis of bone deposition in the osteoarthritic joint.

During vertebrate development, cartilage forms a model for many of the bones of the skeleton. This cartilage is replaced by bone (a process termed endochondral ossification) with an accompanying long bone growth until puberty is reached. Cartilage does, however, persist in the adult at specific sites such as the surface joints. In the development of osteoarthritis the endochondral ossification process is reinitiated and leads to a thickening of the bone underlying the cartilage of the joint and to the formation of bony spurs at the joint margins. The presence of bone in regions of the joint which are usually covered by cartilage reduces the ability of the joint to withstand load and contributes to the destruction of the joint. Research in the laboratory of Mike Grant, Ray BootHandford (Senior Lecturer in Molecular Biology), Gillian Wallis and Tony Freemont (Professor of Osteoarticular Pathology) has identified specific genes that are switched on and off during the endochondral ossification process. These genes are being systematically examined to determine their role in the very precise regulation of the transition of cartilage to bone during normal development and whether they could be responsible for the inappropriate bone formation in the development of osteoarthritis. Inhibition of these genes or their products could specifically inhibit the deposition of new bone in the osteoarthritic joint and thereby prevent some of the consequences of the condition.

* arc is spending more that £1m on funding Professor Grant and his team's work.

Although Professor Grant's work is unlikely to lead to any major clinical breakthroughs for at least a decade, his research into identifying the genetic defects which underlie osteoarthritis could in the long term, have a significant impact, and marks a change in focus from previous scientific approaches.

"The problem has been that there have been no new novel strategies and ideas about how to investigate osteoarthritis," said Professor Grant. "Much of the work in OA is about how joints break down and looking at that. Which has had the effect of stultifying research for 20 years. There have been no major advances – apart from in pain control, management of the disease, and recognition of the need to keep mobility going.

"In terms of looking at the fundamental basic science, we have got a bit stuck. As a consequence there has been more emphasis and more hype on rheumatoid arthritis and other auto-immune diseases.

"So we like to think that this is a new approach; trying to understand the genetics of OA possibly opens up new approaches to therapy, although it's early days. The new technology of human molecular biology is opening up new ways of looking at things which we would never have thought possible a few years ago."