Modulation of inflammatory processes as treatment strategy in osteoarthritis

点击翻译按钮获取中文摘要

Osteoarthritis (OA) is by far the most prevalent of the joint diseases. There are currently no therapies to halt OA onset or progression. The individual and socioeconomic impact of OA is continuing to grow as the population ages. Finding effective disease-modifying therapies for OA is an international medical research priority. While OA has previously been considered an arthropathy defined by “wear and tear”, there is burgeoning evidence that cellular and molecular pathways are driving disease onset and progression. Inflammation is associated with significantly increased risk of rapid progression of cartilage loss in knees with early OA, and a 3-fold increase in odds of cartilage loss over 30 months follow-up in knees without pre-existing OA. Inflammation is not the byproduct but may actually play a pivotal role in initiating the OA process and its progression. The specific inflammatory events in OA, their change with time and the difference from “non-OA-inducing” inflammation, have yet to be fully elucidated. This proposal aims to establish which components of the OA synovial inflammatory process are critical, thereby identifying new drug targets for treatment of the disease. Determining whether reduction of inflammation has disease-modifying effects in OA has been identified among the highest priority research agendas in the field. Using a surgical model of OA in mice we have identified significant differences in the number of macrophages and T-lymphocytes between OA-inducing and non-inducing synovitis. This novel data suggests there may be unique cellular targets and windows of opportunity to avoid the initiation of OA and to halt the progression of established disease. The current research proposal will build upon these findings, test the therapeutic utility of depleting specific inflammatory cells, and provide the platform for initiating human clinical trials for the treatment and prevention of OA through translating out pre-clinical work.