Grant: Project Grant

Arthritis refers to several related conditions that affect joints, causing pain, inflammation and swelling. Osteoarthritis (OA) is the most common form of arthritis and occurs when there is damage in and around the joints, which the body cannot repair. Currently there is no cure for OA and its progression significantly affects an individual's quality of life. OA affects nearly 4.6 million Canadians and is expected to increase to about 7.5 million by 2036. Despite much research effort, the causes and factors involved in OA are not fully understood. Transforming growth factor (TGF)-beta is a protein made in many tissues of the body and there is ample evidence to indicate that its abnormal action in cartilage is involved in the OA disease process. Our research has shown that TGF-beta can have both beneficial and harmful effects on cartilage cells (chondrocytes) depending on the type of "receptor" it uses. In particular, we have shown that TGF-beta will promote healthy cartilage by acting through one type of chondrocytes receptor (known as ALK5) but gives rise to OA-like features when acting through another receptor (ALK1). We have also shown that certain molecules such as TGF-beta co-receptors can influence whether TGF-beta acts through ALK5 or ALK1 receptor. Thus we will examine the role of two co-receptors called endoglin and CD109 in regulating the activity of ALK5 and ALK1. Our goal will be to unravel the mechanism involved in the abnormal action of TGF-beta in chondrocytes and to manipulate the activity of proteins (such as ALK1 and co-receptors) to regulate TGF-beta action, in order to promote cartilage repair. The experiments will be performed using cell and animal models of OA. We expect that findings from the proposed research may lead to the development of innovative therapeutic strategies for the treatment of this debilitating disease.