title: Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients.
abstract: BACKGROUND
  The epidermal growth factor (EGF) and EGF receptor (EGFR) families play important roles in the hyperplastic growth of several tissues as well as tumor growth. Since synovial hyperplasia in rheumatoid arthritis (RA) resembles a tumor, involvement of the EGF/EGFR families in RA pathology has been implied. Although several reports have suggested that ErbB2 is the most important member of the EGFR family for the synovitis in RA, it remains unclear which members of the EGF family are involved. To clarify the EGF-like growth factors involved in the pathology of RA, we investigated the expression levels of seven major EGF-like growth factors in RA patients compared with those in osteoarthritis (OA) patients and healthy control subjects.
  
  
  METHODS
  The expression levels of seven EGF-like growth factors and four EGFR-like receptors were measured in mononuclear cells isolated from bone marrow and venous blood, as well as in synovial tissues, using quantitative RT-PCR. Further evidence of gene expression was obtained by ELISAs. The proinflammatory roles were assessed by the growth-promoting and cytokine-inducing effects of the corresponding recombinant proteins on cultured fibroblast-like synoviocytes (FLS).
  
  
  RESULTS
  Among the seven EGF-like ligands examined, only amphiregulin (AREG) was expressed at higher levels in all three RA tissues tested compared with the levels in OA tissues. The AREG protein concentration in RA synovial fluid was also higher than that in OA synovial fluid. Furthermore, recombinant human AREG stimulated FLS to proliferate and produce several proinflammatory cytokines, including angiogenic cytokines such as interleukin-8 and vascular endothelial growth factor (VEGF), in a dose-dependent manner. The VEGF mRNA levels in RA synovia and VEGF protein concentrations in RA synovial fluid were significantly higher than those in the corresponding OA samples and highly correlated with the levels of AREG.
  
  
  CONCLUSIONS
  The present findings suggest that AREG functions to stimulate synovial cells and that elevated levels of AREG may be involved in the pathogenesis of RA.
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Sakuradai 18-1, Sagamihara, Kanagawa 228-8522, Japan. shoji.yamane@shionogi.co.jp.
authors.forename: Shoji
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authors.lastname: Yamane
authors.forename: Satoru
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authors.lastname: Ishida
authors.forename: Yukie
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authors.lastname: Hanamoto
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authors.forename: Riako
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authors.lastname: Masuda
authors.forename: Konagi
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authors.lastname: Tanaka
authors.forename: Noriyuki
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authors.lastname: Shiobara
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamane
authors.forename: Toshihito
authors.initials: T
authors.lastname: Mori
authors.forename: Takuo
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authors.lastname: Juji
authors.forename: Naoshi
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authors.lastname: Fukui
authors.forename: Tsunetoshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochi
authors.forename: Ryuji
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authors.lastname: Suzuki