Project 445209

Osteoarthritis (OA) is a disease that occurs when joint structures, including the articular cartilage that protects the ends of bones, degenerate following trauma or due to conditions such as obesity. OA leads to chronic pain and disability and places a significant burden on the Canadian healthcare system and economy. However, there are no therapies available that can slow or reverse disease progression. Our previous studies have shown that gene therapy vectors can be used to deliver therapeutics directly to affected OA joints for an extended period. Using this approach, we have shown that a gene therapy vector expressing IL-1 receptor antagonist (IL-1Ra) - an anti-inflammatory molecule - can slow disease progression in small and large animal models of injury-induced OA. We also showed that delivery of the joint lubricant proteoglycan 4 in combination with IL-1Ra provided greater therapeutic effects than either gene therapy alone. Despite these successes, joint inflammation was not entirely resolved by either strategy, and efficacy was eventually lost. Thus, broader inhibition of inflammation may be necessary to curb OA progression, or other factors that drive inflammatory resolution may be required for tissue repair. This proposal will examine whether blocking multiple inflammatory factors simultaneously during active inflammation can better slow OA progression in mouse models of injury-induced disease. We will also explore inflammation-responsive switches to activate the delivery of regenerative factors to promote tissue repair only in the context of injury. In parallel, since little research has examined gene therapies for obesity-induced OA, we will investigate whether these anti-inflammatory strategies can slow disease progression in diet-induced mouse models of early-onset disease. Importantly, this will reveal the role of inflammation in the pathogenesis of OA resulting from various causes, including trauma and obesity.