| Abstract |
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and affects almost 1% of the population. Differentiated embryo-chondrocyte expressed gene-1 (DEC1) has been associated with both osteogenesis and osteoclastogenesis. RA condition is marked by inflammatory hyperplasia, and DEC1 is known to support inflammatory reactions and implicated in antiapoptosis and cell invasion. Here, our goal was to test the hypothesis that DEC1 enhances RA development induced by collagen-induced arthritis (CIA), a well-recognized protocol for developing RA animal models. DEC1+/+ and DEC1-/- mice were subjected to CIA protocol and the development of RA condition was monitored. We found that CIA robustly induced RA phenotypes (e.g., synovial hyperplasia) and greatly increased the expression of proinflammatory cytokines such as TNF-α. However, these changes were detected in DEC1+/+ but not DEC1-/- mice. Interestingly, these very cytokines strongly induced DEC1, and such a dual role of DEC1, as an inducer for and being induced by proinflammatory cytokines, constitutes a DEC1-amplifying circuit for inflammation. Knockdown of DEC1 in human MH7A cells strongly decreased cell migration and invasion as well as the expression of genes related to RA phenotypes. The combination of DEC1-directed migration and invasion in vitro with synovial hyperplasia in vivo mechanistically establishes cellular bases on how DEC1 is involved in the development of RA phenotypes. In addition to inflammatory signaling, DEC1 functionally interacted with PI3KCA(p110α)/Akt/GSK3β, Wnt/β-catenin and NFATc1. Such engagement in multiple signaling pathways suggests that DEC1 plays coordinated and integral roles in developing RA, one of the most common autoimmune diseases.
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