Despite the immense clinical and socioeconomic burden of osteoarthritis (OA), there are still no tests to predict or diagnose early disease, and no treatments to slow or reverse it. One of the obstacles to studying early OA is pinpointing the onset of an initially asymptomatic disease. Joint injury is the major risk factor for OA: around 50% of those sustaining a significant knee injury will develop the disease. Models of joint tissue injury have allowed our group to investigate the very earliest cell signalling events and molecular changes following injury which precede, and perhaps lead to, the development of OA. My group focusses on translating these findings into the human, and understanding their relevance to disease.
1. Identifying novel biomarkers for OA risk following joint injury
Individuals in KICK (the Knee Injury Cohort at the Kennedy) have been recruited immediately after their knee injury and are being followed for 5 years. We want to know whether strongly regulated, candidate molecules from pre-clinical studies are also detectable immediately after human joint injury, and if so, whether measuring this initial molecular response might allow us to predict later disease. We are also interested in the effects of altered or excessive joint loading and the effect of modifying or altering this, for example through splinting or surgery.
This translational work is essential to investigate and validate new molecular targets from the laboratory as potential targets for new therapies. We can also explore broader questions of clinical, physiological or genetic risk in these cohorts. Our aim is to develop a ‘risk profile’ which takes in to account the biological injury response in addition to clinical and imaging features to define an individual’s risk of future OA following joint injury.
2. Biomarkers for early OA
A frequent clinical scenario is the development of symptomatic OA before abnormalities can be seen on X-ray, the current ‘gold standard’ diagnostic test. We need to be able to define specific molecular or imaging changes which reliably predate X-ray change: detecting early disease may, in the same way as has occurred in inflammatory arthritis, allow us to intervene in a timely way to prevent disease progression and joint damage.
3. Targeting treatment to ‘at risk’ groups for clinical trials in OA
Given the typically slow progression of OA, the targeting of new treatments to groups at high risk of disease and/or progression is one way of reducing the size and related cost of clinical trials in OA, and improving their efficiency. The potential for individuals with a history of joint injury or other high OA risk to form a novel group for interventional clinical trials is being assessed as part of our work.
4. Single and multi-centre clinical trials in OA
Our work in this area to date has focused on hand OA. We have recently completed an NIHR-funded study examining the effects of interphalangeal joint splinting for painful, deforming hand OA. We are also proud to participate as a site in UK-wide OA clinical trials via the OA Special Interest Group, British Society for Rheumatology.
1. Watt FE, Ismail HM, Didangelos A, Peirce M, Vincent TL, Wait R, Saklatvala J (2012) Src and fibroblast growth factor-2 independently regulate signalling and gene expression induced by experimental injury to intact articular cartilage. Arthritis and Rheumatism, in press
2. Vincent TL & Watt FE (2010) Osteoarthritis. Medicine 38(3), 151-156.
3. Alexander S*, Watt F*, Sawaji, Y, Hermansson M, Saklatvala J (2007) Activin A is an anti-catabolic autocrine cytokine of articular cartilage whose production is controlled by FGF-2 and NFκB. Arthritis and Rheumatism 56 (11), 3715-3725 *Joint first authors
4. Watt FE, James OFW, Jones DEJ (2004) Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. Quarterly Journal of Medicine 97(7), 397-406
5. Agarwal K, Jones DE, Watt FE, Burt AD, Floreani A, Bassendine (2002) Familial primary biliary cirrhosis and autoimmune cholangitis. Dig liver dis 34(1), 50-52
6. Jones DEJ, Watt FE, Grove J, Newton JL, Daly AK, Gregory WL, Day, CP, James OFW, Bassendine MF. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis (1999). Journal of Hepatology 30(2), 232-6