Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis.
We previously reported that follistatin-related protein (FRP)/TSC-36 was one of the target antigens of autoantibodies in rheumatoid arthritis (RA) and that the appearance of serum autoantibodies to FRP correlated to disease activity in RA. However, the significance of FRP in autoimmunity remained to be explained due to the unknown function of FRP. Here, we disclose in part the function of FRP. Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)-1, MMP-3 and prostaglandin E(2), potent agonists of joint destruction 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 MMP-1 and MMP-3 caused by FRP. Therefore, FRP and its autoantibody can be regarded as defensive and offensive factors respectively in rheumatoid arthropathy. The major epitope of autoantibodies to FRP was mapped to the sequence LKFVEQNE (residues 169-176) and homologous sequences were found in proteins from Escherichia coli, Epstein-Barr virus, etc. FRP and its autoantibody may provide some clues to elucidate the process of disease development and a new approach to the design of therapeutics in RA.
Tanaka
Masao
M
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Ozaki
Shoichi
S
Kawabata
Daisuke
D
Kishimura
Masaaki
M
Osakada
Fumio
F
Okubo
Mitsuo
M
Murakami
Masao
M
Nakao
Kazuwa
K
Mimori
Tsuneyo
T
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects*; D004195:Disease Models, Animal; D000939:Epitopes; D038702:Follistatin-Related Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D038702:Follistatin-Related Proteins