Can bioactive compounds from the diet prevent the onset or slow the progression of osteoarthritis?

Osteoarthritis is a disabling joint disease where the cartilage is destroyed leading to pain and immobility. There is a lack of medicines to treat osteoarthritis, and since the elderly population are more likely to have severe osteoarthritis, this will be an increasing problem. Despite many years of research, there are no drugs available which can slow or stop the progression of osteoarthritis. In part, this is due to the fact that drugs for use in any disease which is not life threatening must be very safe (i.e. have few side effects). Also, the costs of running clinical trials in osteoarthritis are prohibitive. There is a need to develop new strategies to combat this disease. The connection between diet and osteoarthritis has been explored to some extent. The high intake of some foodstuffs has been linked a slower progression of the disease. These analyses are imperfect since diet is recorded via a retrospective questionnaire across a long time period. Nevertheless, they prove the concept that diet can influence joint health. There are many compounds found in food which have biological activities. To date, we have focused on two compounds: sulforaphane which is found at high amounts in broccoli and other related vegetables; diallyl disulphide which is found at high amounts in garlic. Both of these compounds have been investigated for activity in other diseases e.g. heart disease and cancer, but have not been looked at in terms of arthritis. We have added sulforaphane and diallyl disulphide to our laboratory models of the cartilage destruction that is a key facet of osteoarthritis. We have shown that they are effective in slowing or preventing cartilage destruction in these. We have also added these compounds to human cartilage taken from patients with osteoarthritis and maintained in the laboratory and shown that they slow destruction. The objectives of this study are therefore: to refine and improve our work to identify which foods are associated with protection from osteoarthritis; to continue to identify the components of these foods which will prevent or slow cartilage destruction; to test these compounds in a variety of laboratory models using cells or tissues from patients with osteoarthritis; to undertake studies in man to find out whether these compounds get into the joint and/or cartilage tissue in appropriate amounts to slow cartilage destruction. These studies are essential ahead of a full-scale clinical trial in human osteoarthritis and represent an exciting possibility in the prevention and treatment of this disabling disease.

Osteoarthritis (OA) is a degenerative joint disease characterised by degradation of articular cartilage and is a leading cause of disability in the UK. Two major risk factors for OA are increasing age and obesity, thus demographic trends highlight OA as an mounting health and economic problem. There are currently no effective disease-modifying drugs to treat OA and drug development in this area is difficult. A strategy which focuses on bioactive compounds in the habitual diet to prevent onset or slow progression of OA offers a promising alternative strategy. In preliminary studies, we used epidemiology in the UK Twin Registry to identify protective associations between diet and OA. This led us to identify compounds from both allium and cruciferous vegetables which blocked cartilage destruction in our laboratory models. Our hypothesis is that bioactive compounds in the habitual diet have the potential to prevent the onset and/or slow the progression of OA. This proposal aims to extend and refine epidemiology using a co-twin case-control study in the Twins UK database, with more detailed dietary assessment and focusing on OA discordant twins. We will also examine prospective data in the EPIC Norfolk cohort, identifying patients who have progressed to OA ascertained by joint replacement. We will use our earlier laboratory data and these epidemiology studies to test the relative potency of key bioactive compounds from relevant foods in both primary human articular chondrocytes in culture and also in human cartilage explant assays of tissue catabolism. This will culminate in a pilot scale proof-of-principle study in man to examine the levels and functional activity of bioactive metabolites attained in human cartilage after consumption of food containing the bioactive. Ultimately, this will inform the design of a full scale human intervention trial enabling us to translate findings from both an industrial and public health perspective.

Data coming from these studies will inform the development of functional foods or beverages containing optimal doses of bioactive compounds. We would aim to take this forwards with an appropriate industrial partner from the DRINC consortium and with input from the Research, Enterprise and Engagement Office at UEA. Clark and Cassidy have previously worked in industry (AstraZeneca and Unilever respectively), and several team members have funding or current collaborations with industry for both basic biology and clinical research. Data from this project would allow us to refine dietary reference values and provide advice to consumers on optimal intake of specific fruits and vegetables for the prevention of osteoarthritis. We would aim to collaborate with government agencies to translate these findings from a public health perspective. We will also aim to work in patient education in this area with e.g. Arthritis Research UK (previously the Arthritis Research Campaign) and appropriate international charities. Experience from this project will also inform future research in the impact of diet on osteoarthritis and in optimizing clinical trials in this disease. Cassidy, MacGregor and Donell have a wealth of experience in trial design and management. This expertise could be made available to both other academic groups and also to industry (e.g. via the MRC Therapeutic Capability Cluster initiative or other appropriate channels) in order to maximise the potential for any chondroprotective agent to go through the developmental pipeline. It may also be possible to enhance the levels of bioactive compounds present in standard plant strains. This has been achieved within the Norwich Research Park e.g. using plant breeding to create a high glucosinolate, so-called 'super broccoli' (Prof Richard Mithen, Institute of Food Research) or e.g. with tomatoes engineered to produce high levels of anthocyanins with demonstrable efficacy in animal models of disease (Dr Cathie Martin, John Innes Centre). Any potential for commercialisation of such plants would also be investigated in partnership with the InCrops Enterprise Hub, based on the Norwich Research Park, which aims to provide business support and commercialisation opportunities in the alternative and non-food crops sector in the East of England. The investigators have collaborated productively in the past (see Track Record in Case for Support) and will work together to achieve impact in the current study. Between them, they have experience in working for and with industry, the health service, consulting, forming and advising on policy and engagement with the public. The research coming from this study will be disseminated via meetings, publications and collaborations. This includes the DRINC dissemination meetings where both academic and industry partners will have access to early data. In order to communicate the outcomes of this study more widely, a website will be established, highlighting meeting abstracts, talks and publications. This will link from each of the investigators institutional web pages, and also link out to relevant investigators across the Norwich Research Park. UEA also has an experienced press office who will manage communication of the study outcomes with the media in an appropriate and clear manner. The PI and other members of the team have undergone locally organised media training in order to support this, and have experience in being interviewed by the press, radio and television.