Rheumatology Advance Access originally published online on August 16, 2005
Rheumatology 2005 44(11):1374-1382; doi:10.1093/rheumatology/kei023
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Citrullination of fibronectin in rheumatoid arthritis synovial tissue
1 The Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1–7–22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa, 230-0045 and 2 Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, 3 Medicinal Biotechnological Center, Shangdong Academy of Medical Sciences. Jiangshi Road 89, Jinan, Shandong, 250062, P. R. China and 4 Graduate School of Medicine and Faculty of Medicine Kyoto University. Kyoto, Japan.
Correspondence to: X. Chang. E-mail: xchang{at}src.riken.go.jp, changxt{at}126.com
Objectives. Citrullination, catalysed by peptidylarginine deiminase (PAD), is the post-translational modification of peptidylarginine to citrulline, which is intimately involved in the pathogenesis of rheumatoid arthritis (RA). Fibronectin (Fn), a large glycoprotein, is expressed at high levels in arthritic joints and it mediates various physiological processes through interactions with cell-surface integrin receptors and growth factors. We investigated the citrullination of Fn and its potential contribution to the pathogenesis of RA.
Methods. We localized Fn expression and citrullination in RA synovial tissue by immunohistochemistry, immunoprecipitation and western blotting. We also determined levels of citrullinated Fn in plasma from RA patients using sandwich enzyme-linked immunosorbent assay (ELISA). After incubating Fn with rabbit skeletal muscle PAD, we examined the binding ability of citrullinated Fn to vascular endothelial growth factor (VEGF) and integrin ß1 using a solid-phase receptor binding assay as well as the effect of the citrullinated Fn on apoptosis using cultured HL-60 cells.
Results. Immunohistochemistry and western blotting analysis indicated that Fn formed extracellular aggregates that were specifically citrullinated in RA synovial tissue. No Fn deposits were observed in synovial tissues of osteoarthritis (OA). Sandwich ELISA detected higher levels of citrullinated Fn in plasma from patients with RA than from healthy controls or those with systemic lupus erythematosus. Following citrullination in vitro, the affinity of Fn for VEGF increased, but binding activity to integrin ß1 decreased and Fn no longer stimulated the apoptosis of monocytes induced from cultured HL-60 cells.
Conclusions. Our results suggest that the citrullination of Fn is a specific event for RA synovium, although others have detected citrullinated total proteins in inflamed synovial tissue of RA and non-RA patients. Citrullination of Fn could alter interactions between Fn and its receptors and growth factors, consequently contributing to mechanisms of RA pathogenesis such as perturbed angiogenesis and apoptosis.
KEY WORDS: Rheumatoid arthritis, Synovial tissue, Fibronectin, Citrullination, Peptidylarginine deiminase 4 (PADI4, PAD4 or PAD5), VEGF, Integrin ß1
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