Focus on the Kennedy Institute of Rheumatology - research questions answered
Published on 01 October 2008
Modifying glucocorticoids and other drugs to reduce side effects in inflammatory arthritis patients and researching new ways of finding out who is most likely to develop osteoarthritis after an injury are just some of the research questions being addressed at Arthritis Research UK’s West London institute. In the second of three reports, Gillian Riley investigates.
The anti-inflammatory effects of glucocorticoids were discovered as far back as the 1940s by Philip Hench and his collaborators. A physician specialising in rheumatoid arthritis, Dr Hench first treated patients with glucocorticoids in 1948, and saw a remarkable improvement of their symptoms.
Since his pioneering work, which won him the Nobel Prize for medicine, manufactured glucocorticoids have been a mainstay in the treatment of rheumatoid arthritis, asthma and many other conditions. However, these original “wonder drugs” come with two important problems. The first is that they do not always work. For reasons that are not really understood, a few people find that glucocorticoids are not very effective at controlling their flares of inflammation. The second problem is that glucocorticoids may cause side-effects like osteoporosis, a weakening of the bones. Such side-effects can be debilitating and even life-threatening, but they are also unpredictable and difficult to avoid.
Dr Andrew Clark, a senior lecturer at the Kennedy, is investigating the way in which glucocorticoids function at the cellular level to see if their use can be modified so that they work more efficiently with fewer side-effects.
He explains: “Much research has focused on how inflammation is ‘switched on’, but less is known about the ‘off switches’. Like many researchers these days I am increasingly interested in the body’s natural mechanisms for preventing excessive inflammation. For one thing, problems with these natural off-switches might be at the root of chronic inflammatory diseases like rheumatoid arthritis. For another, better understanding of these mechanisms may give us ideas for new treatments. Glucocorticoids are natural hormones produced by the body in response to inflammatory products. They have a crucial role in damping down the inflammatory response, what we call a negative feedback loop. Patients who do not produce sufficient glucocorticoids are less able to control their inflammatory responses and therefore quite prone to inflammatory diseases”.
It is known that inflammatory responses are driven by enzymes called MAP kinases, which promote the production of inflammatory factors such as tumour necrosis factor (TNF). Dr Clark discovered that glucocorticoids are effective at switching off MAP kinases, but they do so in quite an indirect way. They increase the amount of another enzyme, known as a phosphatase, which is able to switch off the pro-inflammatory MAP kinases. Dr Clark believes that the phosphatase may be vital for the control of inflammation by glucocorticoids. He has tested this idea using mice genetically engineered to lack the phosphatase. As predicted, the anti-inflammatory effects of glucocorticoids were impaired in these mice.
“This gives us a new way of thinking about the anti-inflammatory properties of glucocorticoids and how they might be improved,” says Dr Clark. “If we know more about how the phosphatase is produced we may be able to switch it on using lower amounts of glucocorticoids or without using glucocorticoids at all. In that way we would expect to lessen the troublesome side-effects that glucocorticoids can cause. Another interesting idea is that genetic variations in the amount of phosphatase that is produced might help us to understand why some patients are insensitive to the anti-inflammatory effects of glucocorticoids. These drugs are so powerful and effective, but at the same time beset with problems”, Dr Clark concludes. “It is a fascinating idea that we might be able to refine them and improve their safety”.
Specificity is the key
Dr Jonathan Dean, lecturer at the Kennedy, is currently working on TTP, a molecule which controls inflammation at the genetic level. It regulates inflammatory mediators by destabilising the genetic factors controlling them and may play an important role in the development of inflammatory arthritis. Still at the early stages of its development, this project potentially offers effective anti-inflammatory therapy without the side-effects associated with earlier drug developments.
According to Dr Dean, it is vital “to pinpoint the targets very specifically so that we don’t interfere with other mechanisms: biochemical pathways have many branches and TTP provides us with a more specific solution because it targets a molecule right at the tip of one of these branches."
Dr Dean points out that previous attempts to develop new therapies often failed because they lacked specificity - the targeted molecules influenced several cellular signalling pathways and, blocking them all, inhibited desirable as well as undesirable outcomes.
Dr Dean adds: "A lot of work has to go on behind the scenes for a breakthrough in therapy to be made. It’s very important to keep the translational aspects of research in mind but it should not be forgotten that basic scientific research underpins all of this. Our ultimate goal is to understand and manipulate the molecular machinery so that effective and targeted therapies can be developed.”
Osteoarthritis: a window of opportunity
Statistics show that patients suffering acute meniscal and ligament injuries, such as cruciate tears, carry a dramatically increased risk of developing osteoarthritis (OA) at a later date. At the Kennedy this relationship is being tested in a mouse model, where it is possible to characterise the precise cellular changes that lead to the development of OA following meniscal injury.
Dr Tonia Vincent, clinical scientist, comments: “Orthopaedic surgeons treat a wide range of professional sports injuries and it would be very useful to understand whether changes that occur early in the joint following injury predict later OA development.
“With such a tool, we may be able modulate the early response to injury and prevent or minimise future disease.” She hypothesises that there may be a short window of opportunity - of maybe only a few weeks - in which there is potential to influence the disease course.
“The acute injury response is the tissue response that occurs after injury or surgery,” she explains. “Injured tissue usually undergoes a process that leads to an immune reaction with some inflammation, the clearance of cell debris, and healing of the lesion. This process probably varies according to the individual, and the response may be predictive of future tissue degeneration.”
"OA is not simply a passive wear and tear process"
She adds: “Presently, OA assessment relies on radiographic diagnosis, which is a very crude test, and patients often present late in disease, when there is already substantial cartilage degeneration. Consequently, very little is known about the causes and development of the disease. In the clinic, patients want to know if they should do weight-bearing exercise on an osteoarthritic joint. We know that healthy cartilage thickens with exercise, but also that overuse can be damaging, so we have a lot to learn before we can be confident in our advice.
“From our recent studies in the mouse we do know that OA is not simply a passive ‘wear and tear’ process, and it does have an inflammatory component. We are now making use of genetically engineered mice to determine precisely which pathways are essential in driving disease.”
She is confident that the current research programme will help researchers understand some of the basic mechanisms involved in OA development and it is likely that this will eventually translate into clinical outcomes.