PROJECT SUMMARY:
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-1ß 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-ß1 and
IL-10, but upregulation of pro-inflammatory cytokines (TNF-a and IL-1ß) 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.
