Suppressive autoantibodies in rheumatoid arthritis : construction of gene-modified animals and analysis of their arthrapathy

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We isolated folistatin-related protein (FRP) as a novel autoantigen of rheumatoid arthritis. In order to clarify its pathological role, we tried to construct FRP-transgenic mouse, which is now under way, and tried to elucidate the in vitro and in vivo functions of FRP for synovial cells and their inflammation.Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)1, MMP3 and prostaglandin E2, potent agonists of joint construction in RA. In contrast, autoantibodies to FRP from patients with RA increased their production by blocking FRP activity, probably in the autocrine system. Moreover, FRP down-regulated synovial expression of FOS (c-fos), which seemed responsible for the reduction in MMP1 and MMP3 caused by FRP.We investigated the roles of FRP in a mouse model of arthritis, which was induced in BALB/c mice by injecting anti-type II collagen monoclonal antibody and lipopolysaccharide. Mice were treated with daily intraperitoneal injections of 20 μg of recombinant FRP. This treatment showed significant amelioration of the arthritis severity. Histologic analyses confirmed this finding and revealed the alleviation of cellular infiltration into the synovium as well as cartilage damage. Moreover, array analysis of the gene expression profile in FPR-treated arthritic lesions revealed a reduced expression of the c-fos, ets-2, IL6, MMP3, and MMP9 genes, some of which are thought to be associated with synovial inflammation and joint destruction.These findings from in vitro and in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA.