Rheumatoid arthritis (RA) is a collective term for chronic idiopathic autoimmune inflammatory diseases of synovial joints, which affect an estimated 43 million adults in the US and is a leading cause for disability. RA is associated with elevated levels of a numerous acute phase proteins (APPs), including lipocalin 2 (Lcn2), that drive/dampen the inflammatory response. However, the biological activity, and thus therapeutic potential, of some of the most dynamically regulated APPs remain unexplored. The upregulation of APP such as lipocalin2 (Lcn2) during various inflammatory disorders including RA could be result of inflammatory reactions, but recent studies have shown that upregulated Lcn2 has multifunctional biological activity including bone remodeling function, apart from serving as a disease correlative marker. These studies suggest that it may play a central role during the pathogenesis of RA. More recently, we observed that Lcn2 knockout mice exhibited exacerbated arthritis with severe metacarpal and articular bone damage with elevated levels of pro-inflammatory cytokines (IL-1? and IL-6) when compared to its wild type littermates in serum-transfer arthritis model. In addition, Lcn2 knockout alternative macrophages (M2) exhibited reduced secretion of anti-inflammatory cytokines such as TGF-?1 and IL-10, but upregulation of pro-inflammatory cytokines (TNF-? and IL-1?) by classical macrophages (M1). Taken together, upregulation of Lcn2 during RA may play a crucial role in limiting inflammation and prevent severe bone erosion at the arthritic microenvironment. Therefore, we hypothesize that during arthritis systemically/locally upregulated Lcn2 attenuates the severity of the bone damage by limiting the inflammation and bone erosion. Lcn2 consequently plays an indispensable role in prevention of serious bone damage during autoimmune arthritis. Thus, the goal of this proposal is to investigate the function and mechanism of action of Lcn2 during bone remodeling in IC-mediated autoimmune arthritis. Therefore, establishing the functional role of this dynamically regulated protein will improve our understanding of the pathogenesis of the disease and lead to development of novel therapeutic strategies to treat RA.
Lipocalin 2 (Lcn2) is an innate immune protein produced at high concentrations during various autoimmune inflammatory disorders including rheumatoid arthritis (RA) and may play an essential role in counteracting the extent of bone and tissue damage during RA. We will investigate the function of Lcn2 in RA and possible methods to use Lcn2 to counteract bone and tissue damage in RA.
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