Separating Systemic Inflammation From Obesity in Load-Induced Osteoarthritis

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 DESCRIPTION (provided by applicant): Osteoarthritis is classically defined as a non-inflammatory arthritis caused by excessive mechanical loading on the joint/cartilage. Osteoarthritis is also linked to obesity, which is commonly attributed to increased joint load caused by body weight. Multiple lines of evidence suggest that, in addition to mechanical loading, there are non-mechanical contributors to the development of osteoarthritis. Low-grade chronic systemic inflammation, associated with obesity and the metabolic syndrome, has been implicated as a non-mechanical contributor to osteoarthritis. However, the co-occurrence of obesity and systemic inflammation in most animal models and patients has so far made it difficult to separate the effects of the two factors on osteoarthritis. The proposed Exploratory/Developmental Research project is based on the hypothesis that low-grade chronic systemic inflammation originating in the gut enhances the adverse effects of mechanical load on the development of osteoarthritis. We propose separating the effects of systemic inflammation from obesity using the TLR5 deficient mouse, which spontaneously develops gut flora dysbiosis leading to gut inflammation, low-grade chronic systemic inflammation and a metabolic syndrome-like phenotype. Using a load-induced osteoarthritis model and the fact that inflammation in the TLR5 deficient mouse originates in the gut rather than from obesity, the project includes one aim: to determine the relationship between applied load magnitude and development of osteoarthritis in the TLR5 deficient mouse under three conditions: mild inflammation/mild increased body weight (natural state), mild inflammation/normal body weight (limit fed), and normal inflammation/normal body weight (antibiotic treated). Our findings will tes the idea that systemic inflammation influences susceptibility to osteoarthritis even in the absence of obesity and has the potential to provide the first evidence that changes in gut microbiota (the upstream cause of the TLR5KO phenotype) can influence susceptibility to osteoarthritis.