Differential regulation of c-Met signaling pathways for synovial cell function.
Differential regulation of c-Met signaling pathways for synovial cell function.
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DOI：
10.1186/2193-1801-3-554
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Iwasaki T
中科院分区：
文献类型：
--
作者：
Shibasaki S;Tsunemi S;Kitano S;Sekiguchi M;Sano H;Iwasaki T
我们以前证明，阻断肝细胞生长因子（HGF）受体，c-Met，使用肝细胞生长因子拮抗剂，NK 4，抑制类风湿性关节炎（RA）模型小鼠关节炎。在本研究中，我们研究了c-Met信号在滑膜细胞功能中的作用。我们证明了RA患者的滑膜组织和人RA滑膜细胞系MH 7A细胞表达HGF和c-Met。与骨关节炎滑膜相比，RA滑膜中的HGF和c-Met表达增加，表明RA滑膜细胞中的c-Met信号传导增加。c-Met抑制剂SU 11274可抑制HGF刺激的MH 7A细胞中ERK 1/2和AKT磷酸化。MEK和PI 3 K抑制剂抑制MH 7A细胞产生基质金属蛋白酶-3（MMP-3）、血管内皮生长因子（VEGF）和前列腺素E2（PGE 2），表明c-Met-MEK-ERK和c-Met-PI 3 K-AKT通路参与正向调节MH 7A细胞功能。尽管SU 11274抑制MMP-3和VEGF的产生，但它增强了MH 7A细胞的PGE 2产生，这表明c-Met信号的负调控（独立于MEK-ERK和PI 3 K-AKT通路）参与了PGE 2的产生。阻断c-Met信号传导可能在治疗上有用，通过抑制VEGF和MMP-3的产生来抑制血管生成和软骨和骨破坏，同时增强RA中滑膜细胞中PGE 2的产生。
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.
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影响因子：
--
作者：
Kitano, M;Hla, T;Sano, H
通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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