title: Differential regulation of c-Met signaling pathways for synovial cell function.
abstract: We previously demonstrated that blocking the hepatocyte growth factor (HGF) receptor, c-Met, using a HGF antagonist, NK4, inhibited arthritis in a rheumatoid arthritis (RA) model mice. In the present study, we investigated the role of c-Met signaling in synovial cell function. We demonstrated that synovial tissues from RA patients and MH7A cells, a human RA synovial cell line, expressed HGF and c-Met. HGF and c-Met expression in RA synovium was increased compared to osteoarthritis synovium suggesting increased c-Met signaling in RA synovial cells. The c-Met inhibitor, SU11274, inhibited ERK1/2 and AKT phosphorylation in HGF-stimulated MH7A cells. MEK and PI3K inhibitors suppressed production of matrix metalloproteinase-3 (MMP-3), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) by MH7A cells, suggesting that c-Met-MEK-ERK and c-Met-PI3K-AKT pathways are involved positively regulating MH7A cell function. Although SU11274 suppressed MMP-3 and VEGF production it enhanced PGE2 production by MH7A cells suggesting that negative regulation by c-Met signaling, independent of the MEK-ERK and PI3K-AKT pathways, is involved in PGE2 production. Blocking c-Met signaling may be therapeutically useful to inhibit angiogenesis and cartilage and bone destruction by inhibiting VEGF and MMP-3 production, while enhancing PGE2 production in synovial cells in RA.
authors.affiliation: General Education Center, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, 650-8530 Japan ; Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501 Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shibasaki
authors.affiliation: General Education Center, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, 650-8530 Japan.
authors.forename: Sachi
authors.initials: S
authors.lastname: Tsunemi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501 Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501 Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sekiguchi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501 Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501 Japan ; Division of Pharmacotherapy, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, 650-8530 Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwasaki
keywords: Hepatocyte growth factor; Rheumatoid arthritis; Synovial cell; c-Met