A computational study of adiposity-associated factors in the inflammatory process of osteoarthritis

Chronic inflammation is a key factor in the degenerative changes of osteoarthritic joints. Obesity significantly raises the risk of osteoarthritis (OA), since excess body fat (adipose tissue) not only systemically increases the level of inflammation but also locally stimulates the inflammatory responses within osteoarthritic joints. In this context, physical activity is a practical approach in OA prevention and intervention, whereas current therapeutic strategies remain empirical and lack patient-specific tailoring. This makes it challenging to determine the appropriate dose and timing of physical activity therapy for diverse individuals. Building on our previous work of an adipokine-mediated inflammation model, this study aimed to analyse the effects of obesity and physical activity on OA inflammation by parameterising the inflammatory activities. In this model, five key mediator groups (pro- and anti-inflammatory cytokines, matrix metalloproteinases, adipokines and fibronectin fragments) were included. A global sensitivity analysis was conducted in the estimated parametric space and revealed the critical role of adiposity-associated factors in regulating inflammation. In addition, the inflammatory activities were simulated by tuning two adiposity-associated parameters, body mass index (BMI) and physical activity level (PAL), factoring in a simulated injury. The effectiveness of three physical activity intervention strategies was assessed by examining the inflammatory responses of the representative cases with four BMI profiles. A marked sensitivity to the timing (window period) of physical activity implementation was found. Results underscored the importance of accounting for both the adiposity level and the extent of tissue damage when designing intervention strategies of physical activity and optimising their timing for managing OA inflammation. This novel computational study analyses the adiposity-associated effects of physical activity on OA inflammation, illustrating that the effective window period of physical activity interventions varies from 0 to 15 months, depending on the level of adiposity and mechanical damage. Outcomes from the evaluation of the time window can strategically contribute to optimising physical activity interventions for the management of OA risk at an early stage.