論文

国際誌
2021年1月5日

Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis.

Rheumatology (Oxford, England)
  • Masahiro Hosonuma
  • ,
  • Nobuhiro Sakai
  • ,
  • Hidekazu Furuya
  • ,
  • Yutaro Kurotaki
  • ,
  • Yurie Sato
  • ,
  • Kazuaki Handa
  • ,
  • Yusuke Dodo
  • ,
  • Koji Ishikawa
  • ,
  • Yumi Tsubokura
  • ,
  • Takako Negishi-Koga
  • ,
  • Mayumi Tsuji
  • ,
  • Tsuyoshi Kasama
  • ,
  • Yuji Kiuchi
  • ,
  • Masamichi Takami
  • ,
  • Takeo Isozaki

60
1
開始ページ
408
終了ページ
419
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/rheumatology/keaa310

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-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/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 µCT, 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.

リンク情報
DOI
https://doi.org/10.1093/rheumatology/keaa310
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32770199

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