The exact pathogenesis of arthritis in children or adults is not known, but several cells contribute to the development of autoimmune arthritis including T and B lymphocytes, synovial cells, macrophages, neutrophils and osteoclasts (OC) [1-3]. Identifying common signaling molecules affecting the osteo-immune system and their impact on normal and pathological bone loss may lay the groundwork for future therapies for the variety of diseases such as rheumatoid arthritis. We have found PLC32 to be such candidate. In addition to defective B cell development, PLC32-/- mice are osteopetrotic due to aberrant osteoclast recruitment and function [4] [5]. PLC32 affects the two major RANKL-induced signaling pathways during osteoclastogenesis, namely NF:B and NFAT activation, as well as activation and proper localization of 1v23 integrin adhesive structure in the resorbing cell. Unexpectedly, we also found that PLC32 -/- mice are protected from the insurgence of inflammation associated with two different models of arthritis, the serum induced arthritis which is strictly dependent on neutrophils [6], and the antigen induced arthritis which relays on T cell activation. Although PLC32 is not expressed in T cells, PLC32 controls the ability of dendritic cells (DC) to activate T cells. Antigen pulsed PLC32-/- DC, but not WT DC, fail to initiate an inflammatory reaction when injected into WT mice following a local knee injection of the antigen. Conversely, injection of antigen pulsed WT DC into PLC32-/- mice completely restores the inflammatory response without eliciting osteoclast recruitment and focal osteolysis. These intriguing data position PLC32 as a critical modulator of bone integrity and immune responses during inflammatory arthritis. Based on this observation, we hypothesize that PLC32 is required for DC-mediated T cell activation during inflammatory arthritis. Thus, we aim to study the role of PLC32 in antigen presentation and in DC motility during inflammatory arthritis. We believe that expanding the focus of our original proposal from understanding the role of PLC32 in the OCs to study its effects in DC, may lead to new therapeutic avenues aimed at targeting the inflammatory and osteolytic components of rheumatoid arthritis. This application is in response to Notice NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision.
The overall goal of this proposal is to expand the goals of our original R01 proposal from studying PLC32- mediated regulation of osteoclast differentiation and function to examining the role of PLC32 in DC-mediated T cell activation. Specifically, we aim to investigate the role of PLC32 in antigen presentation and in the recruitment of DCs to the lymph nodes, both critical events required for T cell activation, during inflammatory arthritis. Since the interaction between immune cells and osteoclast is increasingly recognized, identifying common signaling molecules affecting the osteo-immune system and their impact on normal and pathological bone loss may lay the groundwork for future therapies for the variety of diseases such as inflammatory arthritis. .
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