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AB0065 (2021)
HGF/C-MET SIGNALING PROMOTE ANGIOGENESIS THROUGH CXCL16 IN RHEUMATOID ARTHRITIS
M. Hosonuma1,2,3,4, T. Isozaki2, H. Furuya2, Y. Yamazaki5, Y. Ikari2, S. Nishimi2, S. Ishii2, A. Maeoka2, T. Tokunaga2, K. Wakabayashi2, N. Konishi2, S. Fukuse2, K. Ishikawa6, N. Sakai7, K. Inagaki6, T. Kasama2
1Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Department of Clinical Immuno Oncology, Tokyo, Japan
2Showa University, Division of Rheumatology, Department of Medicine, Tokyo, Japan
3Showa University, Division of Medical Oncology, Department of Medicine, Tokyo, Japan
4Showa University, Department of Pharmacology, School of Medicine, Tokyo, Japan
5Showa University School of Pharmacy, Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Tokyo, Japan
6Showa University School of Medicine, Department of Orthopaedic Surgery, Tokyo, Japan
7Showa University, Department of Pharmacology, School of Dentistry, Tokyo, Japan

Background: Hepatocyte growth factor (HGF) binds to the receptor tyrosine kinase c-Met and is a multifunctional cytokine that promotes processes such as cell proliferation, survival, differentiation, migration and angiogenesis [1]. We previously reported that HGF is produced by inflammation in the RA synovium, and activates monocyte migration to the synovium and promotes bone destruction through its own chemotactic effect and enhanced chemokine production in the synovium [2].


Objectives: Therefore, we next aimed to determine the role of HGF in RA angiogenesis.


Methods: The expression of HGF / c-Met in the serum and synovial tissues (STs) of RA patients and controls and human umbilical vein endothelial cells (HUVECs) was evaluated by ELISA and immunostaining. The effect of HGF/c-Met signaling on the promotion of CXCL16 production from HUVECs and RA fibroblast-like synoviocytes (FLSs) was determined by ELISA. To examine the role of HGF in angiogenesis, we performed in vitro Matrigel assays using HUVECs treated with HGF.


Results: HGF in serum in treatment-naive RA patients was significantly higher than that in controls and HGF in serum in treatment-resistant RA showed a significant positive correlation with CXCL16. c-Met were expressed on vascular endothelial cells of RA STs and HUVECs. Stimulation of HUVECs with HGF dose-dependently increased CXCL16 production. c-Met signal inhibition by SU11274 suppressed TNF-α stimulation-enhanced CXCL16 production by RA FLSs in a dose-dependent manner. Furthermore, HGF induced HUVEC tube formation by 1.8-fold.


Conclusion: HGF is produced by inflammation in the RA synovium, and activates angiogenesis through its own potent angiogenic effect and enhanced production of CXCL16 in the synovium. These results indicate that a strategy targeting c-Met signalling may be important for resolving treatment-resistant RA.


REFERENCES:

[1]Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440-3.

[2]Hosonuma M, Sakai N, Furuya H, et al. Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis. Rheumatology (Oxford). 2021 Jan 5;60(1):408-419.


Disclosure of Interests: None declared

Citation: Ann Rheum Dis, volume 80, supplement 1, year 2021, page 1063
Session: Rheumatoid arthritis - aetiology, pathogenesis and animal models (Publication Only)