Diarthrodial joints are lined by a highly specialized tissue called the synovium. In health, the synovial tissue is thought to be the primary synthetic source of the viscous and lubricating synovial fluid that bathes the joint tissues. Further, it is thought to provide nutritional support for the avascular cartilage tissue. In the context of inflammatory arthritis, the synovial lining undergoes profound changes that include infiltration with bone marrow derived lineages, hyperplasia and formation of a pathologic extension, termed 'pannus', that is thought to contribute substantially to the destructive erosions evident in diseases such as rheumatoid arthritis (RA). Despite longstanding appreciation for these synovial functions in health and disease, there exists very little understanding of the molecular regulation of synovial tissue behavior. The PI has a primary career focus on understanding synovial physiology in health and pathophysiology in the context of arthritis. With a goal of gaining insight into the molecular regulation of synovial tissue, we have examined mechanisms by which a member of the cadherin family of homophilic adhesion molecules-cadherin-11-modulates behavior of the predominant mesenchymal lineage of synovial tissue, the synovial fibroblast (FLS). In initial collaborative studies, the expression and function of cad11 on primary human FLS was established. In recently published work (Science 315:1006-1010, 2007), the PI and his colleagues demonstrated that cad11 is expressed on ex vivo primary FLS (and not on bone marrow derived lineages) and functionally modulates adhesive, migratory and invasive capacities of these cells. He also demonstrated that healthy cad11-null mice display a hypoplastic synovial lining thereby providing prima facie evidence for the contribution of cad11 to regulation of FLS behavior in the synovial tissue. Examination of arthritic activity in a mouse model of inflammatory arthritis demonstrates an ameliorated inflammatory response in cad11 null mice thus illustrating a primary involvement of the FLS lineage in the overall pathophysiology of inflammatory arthritis. These studies also showed that cad11 null mice are significantly protected from synovial fibroblast mediated cartilage erosion via pannus tissue. In aggregate, these seminal analyses establish a new paradigm for our perception of the joint lining tissue in health and disease. Now, in ongoing studies of synovial fluid from patients with RA, we have discovered substantial quantities of soluble cad11 thereby implicating cleavage of cad11 as an active mechanism in RA disease physiology. In a 'bedside-to-benchtop' approach, we demonstrate that cad11 is cleaved on synovial fibroblasts to yield a secreted form as well as potentially bioactive cell-associated cad11 fragments. Guided by recently published studies of E- and N-cadherin in other tissues and cell lineages, we hypothesize that regulated cleavage may be directly involved in the molecular pathways regulating FLS (and by implication, synovial tissue) function. This submission proposes a series of investigations to dissect the regulation of cad11 cleavage and functional consequences of this cleavage in primary human synovial fibroblasts. It is anticipated that this translational activity will expand our understanding of disease mechanisms in rheumatoid arthritis as well as provide rationale and context for development of therapeutics directed at cad11 for patients with RA. PUBLIC HEALTH RELEVANCE: We have discovered a unique molecule called cadherin-11 that helps hold the joint lining tissue (called synovium) together in healthy people. In rheumatoid arthritis, we have found that this same molecule (cadherin-11) regulates the behavior of the joint lining tissue. When we block cadherin-11, the synovium no longer attacks the cartilage tissue in our experimental systems. We are working out the mechanisms that regulate cadherin-11 to further understand how this molecule controls the synovial tissue and to understand better how to target cadherin-11 in treating people with RA.