Synergistic combinations of diet-derived bioactives to maintain joint health and prevent osteoarthritis

Osteoarthritis is a degenerative joint disease which is a leading cause of disability in the UK. Approximately 8.5 million people in the UK suffer from moderate to severe OA. These patients are predominantly older than 45 years of age, with the disease often becoming a significant burden in patients over 60 years of age . There is a lack of effective drugs available to treat osteoarthritis and the drugs given for pain relief are often not sufficient . Joint replacement is the only treatment offered to patients at later stages of the disease with 66,436 hip and 77,578 knee replacements due to OA performed in the UK in 2011. Given the current trend toward an older population, osteoarthritis, for which age is an important risk factor, will be an increasing problem for society with 17 million OA patients predicted for 2030 . The ability to slow or stop progression of the disease would significantly improve both quality of life and the economic burden of osteoarthritis.

Despite many years of research, there are no drugs to slow or stop the progression of osteoarthritis. In part, this is because drugs for use in any disease which is not life threatening must be very safe. The costs of running clinical trials in osteoarthritis are prohibitive. There is a need to develop new strategies to combat osteoarthritis.

The connection between diet and osteoarthritis has been explored to some extent. High intake of some foodstuffs has been linked to slower progression of the disease in large population-based studies and these show that diet can influence joint health. However, we need to know much more about how compounds found in the diet work, what are the optimal foods to eat, in what amount and in what combination. When we know this, we can then carefully design controlled human studies to provide clear data from which to advise the public on optimal dietary strategies to both prevent and delay the progression of osteoarthritis.

There are many compounds in food with biological activities. To date, we have focused on sulforaphane, found at high amounts in broccoli and related vegetables. Sulforaphane can prevent cartilage destruction in laboratory models and we have confirmed this ability in a mouse model of osteoarthritis. We have identified the main pathway by which sulforaphane acts in human cartilage cells. We have also identified a number of other compounds, derived from the diet, which have activity in the laboratory assays.

The current application is to gain knowledge of the mechanism(s) by which each diet-derived compound acts to protect cartilage. We will then use this to test mixtures of active compounds to identify the best combination which can protect cartilage and slow or prevent osteoarthritis. We will then test this for its impact upon the human osteoarthritic joint.

When we have collated and analysed all these data, we will then design a trial to investigate the best way to deliver this combination of compounds in the diet in order to protect the joint from osteoarthritis.

Osteoarthritis (OA) is a degenerative disease of the joints characterised by degradation of articular cartilage, thickening of subchondral bone and osteophyte formation. It is a major cause of disability in the UK. There are no effective disease-modifying drugs to treat OA and pain relief is often insufficient. Approx 8.5 million people suffer from OA in the UK, with 71% of these in constant pain. Increasing age and obesity are major risk factors and changing demographics will lead to a large rise in incidence of OA.

Many phytochemicals have been proposed to have positive benefit on joint health and OA, but predominantly these have not been studied in man. The impact of dietary compounds on the joint needs to be studied with increased rigour at scientific and clinical levels to prove efficacy. Our previous research has focused on sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, where we demonstrated efficacy in vitro in cartilage cell and explant assays and in vivo in a mouse model of OA. We are currently undertaking a proof-of-concept trial in man to prove dietary SFN can impact upon the human joint.

We have identified several diet-derived compounds that show efficacy in a surrogate screen of cartilage protection in human chondrocytes. Our hypothesis is that these compounds will display synergy to protect cartilage and prevent or slow the progression of OA. We propose to: (i) investigate mechanism-of-action of 11 diet-derived compounds; (ii) assay synergy between compounds, where this is more likely between compounds which act on different pathways; (iii) test key combinations of compounds in assays of cartilage destruction in vitro; (iv) test one combination in a proof-of-concept human trial to demonstrate action in the human joint.

The identification of a synergistic combination of compounds will allow us to protect intellectual property and design a clinical trial to provide evidence of prevention and slowing OA progression.

These studies will add to our understanding of cartilage protection and the mechanisms of cartilage destruction. They will inform future research on the impact of diet on joint health and osteoarthritis and in optimizing clinical trial designs to address these key health issues. The research will benefit: the academic community (including the named researchers); the food and drink industry; patients with osteoarthritis and any sector of the population at risk from developing osteoarthritis (e.g. after sports injury); clinicians treating osteoarthritis and providing advice on prevention; government agencies setting dietary reference values; charities involved in patient information and education.

A summary of routes to impact include:
1. 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.
2. Data coming from these studies will inform the development of novel ingredients for functional foods or beverages containing optimal doses of bioactive compounds which protect cartilage. In order to be commercially viable, any intervention has to have both efficacy and associated intellectual property. By identifying synergistic mixtures of compounds, we will gain maximum efficacy in cartilage protection and have the ability to protect this.
3. Data from this project may also allow us to refine the five-a-day message and provide more specific 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 to understandable public health messages. We will also aim to work in patient education in this area with e.g. Arthritis Research UK, the British Society for Rheumatology and appropriate international charities.
4. It may also be possible, using either the techniques of genetic engineering or with traditional plant breeding, to enhance the levels of bioactive compounds present in a standard strain. This has already been achieved using plant breeding to create a high glucosinolate, so-called 'super broccoli'.
5. There will be training opportunities for the RA in the areas of dissemination, engagement and exploitation of the study, supported by the investigators and local professional development schemes.

As proof of concept, a mixture, predominantly of flavonoids, baicalin from Scutellaria baicalensis and catechin from Acacia catechu are marketed by Primus Pharmaceuticals for osteoarthritis as Limbrel. These were chosen as inhibitors of cyclooxygenase-2 and 5-lipoxygenase and the preparation has been denoted a 'medical food' by the FDA despite the fact that major sources of these flavonoids are not part of the diet (and indeed Limbrel has recently been associated with severe liver toxicity). This product shows the potential of flavonoids to impact upon the market in OA. This product is only licenced for osteoarthritis patients by prescription but we would see diet-derived compounds showing efficacy in prevention, rather than solely as a therapeutic agent. Several diet-derived flavonoids will be tested in the current application. Such compounds would be best delivered through the diet, in a similar way to sterol-fortified products which impact upon levels of cholesterol. E.g. EFSA recently approved cocoa flavanols to help maintain endothelium-dependent vasodilation, contributing to normal blood flow. They accepted evidence that to gain the claimed effect "200 mg of cocoa flavanols should be consumed daily. This amount could be provided by 2.5 g of high-flavanol cocoa powder or 10 g of high-flavanol dark chocolate, both of which can be consumed in the context of a balanced diet", with the general population as target population. Therefore, it is possible to gain sufficient evidence for EFSA approval of health claims.