TGF-beta type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody.
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.
Sakuma
Michitomo
M
Department of Immunology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Hatsushika
Kyosuke
K
Koyama
Kensuke
K
Katoh
Ryohei
R
Ando
Takashi
T
Watanabe
Yoshiyuki
Y
Wako
Masanori
M
Kanzaki
Mirei
M
Takano
Shinichi
S
Sugiyama
Hajime
H
Hamada
Yoshiki
Y
Ogawa
Hideoki
H
Okumura
Ko
K
Nakao
Atsuhito
A
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
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