Inflammation and mechanical loading in osteoarthritis: An integrative multi-scale approach

There are approximately 350 thousand new cases of osteoarthritis (OA) diagnosed annually in the UK. To date, there is a lack of criteria for early OA identification and for the prescription of disease-modifying osteoarthritis drugs (DMOADs), due to the limited understanding of OA phenotypes and endotypes. This directly affects over 600 million OA patients worldwide, with a higher risk of developing disability among ageing and obese individuals. Emerging research in computational approaches attempted to unravel OA mechanisms driving by both systemic and local factors. However, few computational tools have incorporated both inflammatory and mechanical regulations of obesity in OA. The overall aim of this thesis was to investigate the mechanobiological effects of obesity on OA by developing a novel multi-scale computational approach that integrates obesity-associated inflammation and mechanical loading in OA. A mathematical model of inflammation and obesity in OA was for the first time established and parameterised. The dynamics of inflammatory activities regulated by adipokines was numerically analysed, and the roles of tissue injury, body mass index (BMI) and physical activity level (PAL) in OA inflammation were examined. Based on this novel mathematical model, an integrative multi-scale modelling framework was developed for simulating subject-specific cartilage degeneration in obesity-associated OA. Parameter sensitivity analysis and simulations of cartilage degeneration demonstrated the common and subject-specific variations in degeneration patterns regulated by the mechanobiological effects of obesity. The integrative multi-scale approach developed in this thesis identified critical parameters that could contribute to discover therapeutic targets in obesity-associated OA phenotypes and endotypes. In addition, it is a potential computational tool that can be individualised to assess the subject-specific heterogeneity of OA and predict cartilage degeneration in the context of obesity.