title: TGF-beta type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody.
abstract: Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-beta is expressed at high levels. However, the precise role of TGF-beta in RA remains unclear. We herein demonstrated a causal link between the TGF-beta-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-beta induced IL-6 and vascular endothelial growth factor (VEGF) production by RA synovial fibroblasts associated with nuclear factor-kappa B activation. These effects of TGF-beta on RA synovial fibroblasts were suppressed by TGF-beta type I receptor kinase inhibitor HTS466284. Furthermore, HTS466284 significantly prevented anti-collagen type II antibody-induced arthritis in mice according to the clinical manifestations, histology, tumor necrosis factor-alpha, PDGF and VEGF expression and 5-bromo-2'-deoxyuridine incorporation. These in vitro and in vivo results suggest that TGF-beta plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-beta signaling may thus become an additional strategy for the treatment of RA.
authors.affiliation: Department of Immunology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Michitomo
authors.initials: M
authors.lastname: Sakuma
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Hatsushika
authors.forename: Kensuke
authors.initials: K
authors.lastname: Koyama
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Ando
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Masanori
authors.initials: M
authors.lastname: Wako
authors.forename: Mirei
authors.initials: M
authors.lastname: Kanzaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takano
authors.forename: Hajime
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hamada
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000187:drug effects / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D024043:Collagen Type II; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D018125:Receptors, Transforming Growth Factor beta; D042442:Vascular Endothelial Growth Factors; D000099151:MAP Kinase Kinase Kinase 7