Grant: Operating Grant - PA: Musculoskeletal Health, Arthritis, Skin and Oral Health

Despite extensive research, the mechanisms by which osteoarthritis can be treated still remains a mystery. Our animal and cell based studies suggest that PPARgamma (a biological factor) is an attractive target for the treatment of osteoarthritis. Activation of this biological factor by certain drugs such as rosiglitazone (FDA approved anti-diabetic drug) has been shown to reduce inflammation and symptoms related to osteoarthritis in animal models. However, one of the key problems of these drugs is that they activate not only PPARgamma but also other variety of factors resulting in serious side effects in patients including increased risk of heart attacks. Since these drugs activate other factors, the exact role of PPARgamma in growth and development of cartilage (cartilage is one of the major part of the joint affected in osteoarthritis) and in osteoarthritis still remains unknown. This study will investigate the specific role of this factor in cartilage development and osteoarthritis using genetically modified mice and then we will compare mice data to specimens collected from normal human and osteoarthritis patients. Since cartilage destruction is one of the major process during osteoarthritis, I have generated mice in which PPARgamma is genetically absent only in cartilage. Using these mice we will be able to specifically answer the following questions: (1)Does PPARgamma control growth and development of cartilage? (2)Does PPARgamma control cartilage damage observed during osteoarthritis? (3)Does PPARgamma inhibit inflammation and production of harmful mediators which destroy the bone and cartilage during osteoarthritis? I anticipate that this study will show that PPARgamma is the key target for the treatment of osteoarthritis as it is likely to control the damage of bone and also inflammation observed in osteoarthritis. This project has the potential to generate new therapeutic strategies for the treatment of osteoarthritis and other forms of arthritis