Project 451967

Osteoarthritis (OA) is the most common form of arthritis and affects more than 4 million Canadians. The impacts of OA on affected patients and the society are enormous, both in terms of individual suffering and associated costs to the health care system and economy. However, no satisfying treatments to stop or reverse OA are available. One main reason for this lack of treatments is that we do not understand the underlying molecular and cellular mechanisms well, and therefore have no clear targets for drugs to treat OA. Our recent work has suggested an important role of the protein PGC1alpha in maintaining healthy joints and preventing OA. PGC1alpha is a regulatory protein that controls the activity of many other genes in our cells. When we removed the gene for PGC1alpha from the joints of mice, these mice developed early OA, while their normal littermates still had healthy joints. Therefore, we hypothesize that PGC1alpha maintains cartilage health and prevents progression of OA. We will now examine the role of PGC1alpha in OA through three specific aims. First we will study the role of this gene in different subtypes of OA. We will examine our genetically modified mice (PGC1alpha KO mice) in models of injury-induced (post-traumatic) OA, aging-associated OA, and obesity-induced OA, thereby mimicking the most common risk factors for OA in patients. We will then test the molecular and cellular mechanisms involved in the action of PGC1alpha, using joint cells both from our mutant mice and from human patients. Finally, we will test whether introducing more PGC1alpha into mice protects them from OA after injury, during aging, and in obesity. Together, these studies will determine the role of PGC1alpha in various forms of OA and whether manipulation of PGC1alpha is a promising strategy to treat OA.