Dr Gary Litherland, lecturer in Cell & Cartilage Biology at the University of the West of Scotland, has been investigating the molecular mechanisms that drive cartilage damage in osto-arthritis. His project was funded by a Collaborative Research Grant and was conducted in collaboration with the universities of Glasgow, Newcastle and Strathclyde.
Gary, you’ve been working on a project funded by the Carnegie Trust looking at signalling pathways in Osteo-Arthritis (OA). Could you tell us more about the research?
Firstly, thanks for asking me to talk about what is proving to be a very exciting project, one that is already generating new insights and leading my research in interesting new directions. Joining UWS as a lecturer was a daunting step, but my Carnegie funding has provided me with a vital springboard to establish myself as an independent researcher and build a long-term research strategy.
OA is the most common form of arthritis, in which we see progressive damage to joint tissues including loss of cartilage - the tissue covering the end of our long bones that resists compression and enables them to move within the joint without friction.
Our project is focused on a protein found on the surface of cartilage cells called protease-activated receptor-2 (PAR2), which senses the presence of certain enzymes (proteases) that can break down or modify other proteins. PAR2 seems to be very important in driving cartilage damage in OA, because when PAR2 is absent in an experimental model of the disease, the cartilage is protected against degradation. The project is about trying to work out the molecular changes (signals) that happen inside cartilage cells after PAR2 is activated, since this will give us vital clues as to the mechanisms the receptor uses to cause tissue destruction. Once we fully understand these mechanisms, we can attempt to block the signals, and so help prevent joint damage in OA patients.
Why is OA research so important?
I think most people will know one or more people who suffer from the chronic pain and disability caused by OA. Almost 9 million people in the UK alone have sought treatment for the disease, and a third of all people over 45. The problem is that although clinicians can offer pain relief to patients and promote the benefits of exercise, there is still no effective treatment that can stop or reverse the damage to cartilage and other tissues, so eventually the affected joints need to be replaced by major surgery. Sadly, the problem is growing ever larger. The societal trends of advancing age and obesity are also major risk factors for OA, and so the burden of OA on the NHS continues to get bigger each year.
What are the next steps for your research into osteo-arthritis?
A vital aspect of my Carnegie support has been to enable me to embed expertise in cartilage biology within the bigger programme of OA research developed by the Centre for Musculoskeletal Science (CMS), a consortium of scientists and clinicians with diverse specialities in the west of Scotland (Glasgow, Strathclyde and UWS) all working together to provide a holistic approach to the study of joint diseases.
My Carnegie project work so far is illuminating the pathways and genes that are activated by PAR2 in cartilage and the damaging impact on the tissue, to help identify possible downstream drug targets. Just as important though, is to work out what happens upstream of PAR2 activation. What causes the production of the PAR2 receptor in OA: what is special about a diseased joint that result in this destructive activity? There are lots of enzymes produced in the joint that could be the key switches to ‘turn on’ PAR2 during disease – which are the important ones that are potential new drug targets, and which are ‘innocent bystanders’? Where do these disease triggers come from - the cartilage itself, or interactions with nearby joint tissues? Working with the rest of the CMS team, with access to the wealth of expertise and support this brings, will help me to answer such questions and hopefully find new therapeutic strategies to combat the pain and immobility of OA.
What new therapies could be envisaged in future?
An exciting development is the move toward personalised medicine in OA that will continue to grow. OA is not really one disease but a spectrum, and individual patients may not share the same mechanisms of disease and so won’t necessarily benefit from the same drugs. For instance, inflammation may play a pronounced role in some people, and biomechanical factors in others. There are also likely to be different underlying genetic and epigenetic factors that predispose some people to develop the disease. Discovering these genetic changes is leading researchers to discover brand new and exciting mechanisms that may be exploited to develop new drugs. Using a patient’s own stem cells to regenerate damaged tissue is also an important future goal, although there are still big challenges to overcome.
In any case, it may be unrealistic to expect a single new drug to be effective for all OA patients. However, because PAR2 is known to be involved in three key pillars of the disease; inflammation, tissue destruction and pain, this makes it a very attractive drug target for OA, so our work is geared to developing a future therapy that could be of particular value to patients.
What is your research background and how did you become interested in the biological mechanisms that may contribute to OA?
My career has taken in several university centres of research excellence and given me a broad range of expertise in diverse biological disciplines, and I like to think this allows me to bring a unique perspective to my research on arthritis.
My PhD training was at Leeds, as a microbiologist and biochemist with an interest in complex membrane proteins. This led me to Edinburgh and Dundee to study regulation of membrane transporters that are important in diseases such as cancer and type 2 diabetes, and here I became focused on the cellular signals controlling their activity. Back south of the border in Newcastle, I saw that pro-inflammatory signalling in these diseases also occurred in arthritis, and became interested in how these events increased the level of cartilage-degrading enzymes in OA. Now I’ve been given an opportunity to return to Scotland with UWS, I think I’ve found a home where I can bring my research strengths together, with the goal of preventing PAR2-dependent joint destruction in arthritis.
What advice would you give to Early Career Researchers applying for their first grants?
In today’s challenging climate, I would say that it’s vital to identify and cultivate a supportive network of collaborators who can offer different perspectives and help you get involved in a bigger research picture, whilst you continue to develop your own ideas and unique niche. Trying to do it all alone is tough, not to mention inefficient.
I would look to take full advantage of funding schemes such as the Carnegie Collaborative Grant, which offers a great vehicle to formalise such networks, enabling you to integrate your own expertise with that of other, perhaps more established, researchers while generating key pilot data as the platform to bid for large-scale grant funding when ready.
In my case, thanks to the Trust’s support I’m now an integral member of CMS, embedding cartilage biology as a key dimension of exciting new projects involving a team of research students and staff. This value has been recognised with an honorary appointment at Glasgow University and I’ve recently become Operations Manager in CMS, with a key role in many aspects of group activity, so I’ve definitely managed to get my feet under the table!