Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis
Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis
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DOI：
10.1093/rheumatology/keaa310
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发表时间：
2021-01-01
期刊：
影响因子：
5.5
通讯作者：
Isozaki, Takeo
中科院分区：
文献类型：
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作者：
Hosonuma, Masahiro;Sakai, Nobuhiro;Isozaki, Takeo
目标.为了确定肝细胞生长因子（HGF）在RA生物体液中的表达，HGF在单核细胞迁移中的作用以及c-Met抑制剂savolitinib在关节炎模型小鼠中的治疗作用。采用ELISA和免疫组化法检测RA患者血清、SF和滑膜组织（ST）以及RA成纤维细胞样滑膜细胞（FLS）中HGF/c-Met的表达。为了确定HGF在RA SF中的功能，我们用中和性抗HGF抗体预孵育RA SF，并测定人急性单核细胞白血病细胞系（THP-1）的趋化能力。此外，对用savolitinib治疗4周的SKG小鼠进行检查。RA患者血清中HGF水平显著高于对照组，药物治疗24周后降低。RA患者SF中HGF水平高于OA患者。在RA ST中也观察到HGF和c-Met表达。用TNF-α刺激RA FLS以浓度依赖性方式增加HGF/c-Met表达，c-Met信号抑制抑制fractalkine/CX 3CL 1和巨噬细胞炎性蛋白-1 α/CCL 3的产生。当通过免疫沉淀去除HGF时，RA SF中THP-1的迁移受到抑制。在SKG小鼠中，savolitinib显著抑制了mu CT上的踝关节骨破坏，并减少了抗酒石酸酸性磷酸酶阳性破骨细胞的数量。类风湿关节炎患者滑膜炎症产生的肝细胞生长因子激活单核细胞向滑膜迁移，并通过趋化作用和增强趋化因子的产生促进骨破坏。
Objectives. To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice.Methods. HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks.Results. HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-alpha increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1 alpha/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on mu CT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts.Conclusion. HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.