Differential regulation of c-Met signaling pathways for synovial cell function.

Seiji Shibasaki,Sachi Tsunemi,Masahiro Sekiguchi,Sachie Kitano,Hajime Sano,Tsuyoshi Iwasaki

doi:10.1186/2193-1801-3-554

Seiji Shibasaki, Sachi Tsunemi + Show 4 more

Open Access

https://doi.org/10.1186/2193-1801-3-554

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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.

Highlights

Rheumatoid arthritis (RA) is characterized by an aggressive synovial expansion due to angiogenesis and subsequent destruction of the underlying cartilage and bone (Szekanecz and Koch 2008, Scot et al 2010, Szekanecz et al 2010)
hepatocyte growth factor (HGF) and c-Met expression in the synovium of RA patients To examine whether c-Met signaling pathways are involved in the pathogenesis of RA, we examined the expression of HGF and c-Met in the synovium of OA and RA patients
We demonstrated that MH7A cells, a synovial cell line established from RA patients, expressed HGF and c-Met by Western blot analysis (Figure 1B)

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by an aggressive synovial expansion due to angiogenesis and subsequent destruction of the underlying cartilage and bone (Szekanecz and Koch 2008, Scot et al 2010, Szekanecz et al 2010). Synovial cells produce inflammatory mediators, proteases, and angiogenic growth factors such as prostaglandin E2 (PGE2), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) (Pap et al 2000). MMPs are responsible for the destruction of cartilage and bone in RA joints. MMP-1 and MMP-3 are critical proteases in tissue degradation in RA (Walakovits et al 1992, Green et al 2003). PGE2 plays a major role in angiogenesis through the expression of VEGF in rheumatoid synovium (Ben-Av et al 1995). PGE2 has been shown to trigger bone resorption by osteoclasts (Mino et al 1998) suggesting that the inflammation

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