Rheumatoid arthritis (RA) is a chronic, painful, incurable, and potentially debilitating disease for which effective therapies are still lacking. One of the earliest histopathological features of RA is the increase of blood vessels in the synovium, which is thought to facilitate the infiltration of leukocytes. synovial hyperplasia, and persistent inflammation. Thus. although angiogenesis itself may not be the cause of RA, it can exacerbate the patholobiology of RA. By analogy to studies in tumor biology in which angiogenic inhibitors have been shown to severely restrict tumor growth, it follows that targeting angiogensis in the RA synovium. may be an efficacious therapeutic approach. We propose to study the role of Cyr61, a novel angiogenic inducer. in RA. Cyr61 can also induce expression of matrix metalloproteases (MMPs), enzymes that promote joint destruction. However. the potential role of Cyr6l has not been systematically examined in RA. Our hypothesis is that Cyr6l plays a critical role in the angiogenic response in RA, and may serve as an attractive therapeutic target in this disease. We seek to evaluate the role of Cyr61 in RA in two specific aims. First, we will assess the correlation between Cyr61 expression and angiogenesis in human RA synovium by in situ hybridization and immunohistochemistry. The expression of Cyr61 in inflammatory arthritis will be investigated further in a murine model of collagen-induced arthritis (CIA) using similar approaches. Then we will explore Cyr61 as a potential therapeutic target. We will test whether blockade of Cyr6l function, using monoclonal antibodies or inhibitory peptides, can prevent or ameliorate arthritis and joint destruction.
