Innate Immune Regulation of Inflammation in Osteoarthritis
- Based in the Brighton and Sussex Medical School
- Supervisors: Dr Sandra Sacre, Dr Peter Bush and Dr Sarah Newbury
Application deadline is 4pm, 27 June 2013
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Musculoskeletal disorders are the most common cause of long term disability and are associated with a high cost for treatment due to their chronic nature. The most common musculoskeletal complaint is osteoarthritis (OA), a chronic disease of the joints characterised by low-grade inflammation, cartilage destruction and joint pain 1. It is more commonly diagnosed in elderly patients, thus the incidence and prevalence of OA is expected to continue to increase as the population ages.
OA often starts quietly with no clinical symptoms, thus by the time of diagnosis deterioration of cartilage is already evident. However, it is not just the cartilage that is affected; changes are also observed in the synovial fluid, synovium, tendons, ligaments and subchondral bone. The treatment of OA is particularly challenging. Current therapies include non-steroidal anti-inflammatory drugs which help to reduce the pain and inflammation but they are at best, only modestly effective at decreasing joint destruction, meaning many patients eventually require joint replacement surgery.
Low grade inflammation and synovitis are present in the early stages of OA and are considered to be actively involved in the disease progression and have been associated with pain and the rate of cartilage degradation2,3. This inflammation and subsequent joint destruction is mediated by inflammatory cytokines and matrix metalloproteases (MMPs) released from chondrocytes, infiltrating mononuclear cells and synoviocytes. However, the mechanisms responsible for their production remain unclear. Developing a better understanding of these processes will be essential for improving early diagnosis and the long term treatment of OA.
This study will investigate the contribution of cytosolic innate immune receptors to the production of inflammatory cytokines and MMPs in osteoarthritis samples from early and late stage disease. Members of both the Rig-like receptor and the Nod-like receptor families are up-regulated in OA cartilage compared with healthy neck of femur cartilage4 and in OA synovial fibroblasts when compared to rheumatoid synovial fibroblasts 5. The expression, function and regulation of key receptors from both families will be investigated in patient samples collected from joint arthroscopies or joint replacement surgery.
The project will based at Brighton and Sussex Medical School and will form a collaboration with Dr Peter Bush (University of Brighton) who has expertise in working with chondrocytes and subchondral bone. In addition, several orthopaedic surgeons who already provide joint tissue for an ongoing complementary project examining the role of innate immunity in rheumatoid arthritis will contribute with this project. Understanding the mechanisms sustaining joint damage in osteoarthritis will be a key development towards meeting the needs of an ageing population.
References
1. Loeser, R.F., Goldring, S.R., Scanzello, C.R. & Goldring, M.B. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 64, 1697-1707 (2012).
2. Goldring, M.B. & Otero, M. Inflammation in osteoarthritis. Curr Opin Rheumatol 23, 471-478 (2011).
3. Hill, C.L., et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis 66, 1599-1603 (2007).
4. Radwan, M., et al. Matrix metalloproteinase-13 expression in response to double-stranded RNA in human chondrocytes. Arthritis Rheum (2013).
5. Carrion, M., et al. RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: immune regulation by vasoactive intestinal peptide. Arthritis Rheum 63, 1626-1636 (2011).
