Title: Understanding an endogenous mechanism that protects against osteoarthritis; towards a new paradigm for disease management
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is a serious disease affecting 1 in 3 adults over the age of 45 in the UK. Pain and loss of joint mobility prevent people with OA from carrying out daily activities, with a huge impact on quality of life. OA is associated with heart disease, mental health problems and reduced life expectancy. There are still no drugs to prevent progression of OA and more than 160,000 joint replacements are performed each year in the UK to relieve pain and restore function. People with OA have identified a major need for treatments to reduce symptoms and delay the need for surgery. Previous research has developed our knowledge of how joint damage occurs in OA. We consider that exploring OA from a different perspective, i.e. to understand the inherent molecular pathways that slow or prevent the disease process in some individuals, will pave the way for new personalised treatments for this debilitating condition. Our work has shown that a protein called TSG-6 has protective effects and reduces inflammation in joint tissues. We are developing a potential drug for OA (called Link_TSG6) based on the TSG-6 protein; our research in animal models has shown that Link_TSG6 can protect cartilage from damage and reduce pain. The focus of this proposal is to establish how TSG-6 protein that is made by cells in mobile joints (e.g. the knee) contributes to the natural protection of joint tissues. We will investigate this from the point of disease onset (e.g. when cartilage damage is caused by injury) through to established OA (using tissue donated by people having joint replacements). This multi-disciplinary programme builds on the exciting outcomes of our recent work, using state-of the art techniques to extend into new areas and move closer to a treatment for OA. We aim: (i) to analyse individual cells within joint tissues to determine how the level and location of TSG-6 production affects disease pathways in OA; (ii) to determine how cells in cartilage respond to Link_TSG6 and to identify ‘markers’ in joint fluid that can predict whether patients will respond to Link_TSG6 treatment; (iii) to develop a mouse model of OA where no TSG-6 is made in the joints and determine how this affects disease onset and progression; (iv) to use gene-editing techniques in models of cartilage made from human stem cells to determine how TSG-6 protects against damaging inflammation in cartilage. The intended outcomes will have a major impact on the treatment of OA for individual patients by: (i) addressing the question of why some individuals develop OA while others don’t; and (ii) providing new information to support the development of Link_TSG6 as an OA drug. Our studies, using cartilage donated during knee replacement surgery, indicate that people with OA could be classified as ‘responsive’ or ‘non-responsive’ to Link_TSG6 treatment. Determining the differences between these groups will increase our understanding of the OA process and improve options for diagnosis and treatment, including personalised medicine approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL