A Disintegrin and Metalloprotease 15 is Expressed on Rheumatoid Arthritis Synovial Tissue Endothelial Cells and may Mediate Angiogenesis.

Shinichiro Nishimi,Hiroko Takeuchi,Kuninobu Wakabayashi,Takeo Isozaki,Tsuyoshi Kasama

doi:10.3390/cells8010032

Shinichiro Nishimi, Hiroko Takeuchi + Show 3 more

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https://doi.org/10.3390/cells8010032

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Journal: Cells	Publication Date: Jan 9, 2019
Citations: 10	License type: CC BY 4.0

Affiliation: Showa University

Abstract

A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.

Highlights

We found that A disintegrin and metalloprotease 15 (ADAM15) small interfering RNA (siRNA)‐treated human umbilical vein endothelial cells (HUVECs) showed decreased migration formation in Matrigel in response to Rheumatoid arthritis (RA) Synovial fluids (SFs) compared with non-treated HUVECs
We report here that ADAM15 is overexpressed in RA sera, SFs, and synovial tissues (STs)
ADAM15 level in RA sera was decreased using TCZ therapy. These results indicate that the ADAM15 level in serum correlated with RA disease activity

Summary

Introduction

RA synovium contains high levels of inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, which are major inflammatory mediators that induce and maintain disease processes and abundant inflammatory cells, including infiltrating lymphocytes and monocytes [2,3,4]. A disintegrin and metalloproteases (ADAMs) are membrane-anchored glycoproteins composed of multiple distinct protein modules [7]. One of these is ADAM17, known as TNF-α-converting enzyme (TACE), which is a cell surface protease that has been implicated in the shedding of inflammatory cytokines and growth factors such as IL-6 receptor or epidermal growth factor receptor. ADAM15 is overexpressed in lining cells, endothelial cells, and macrophage-like cells in the sublining layer of RA synovium [11]. We examine the role of ADAM15 in RA angiogenesis

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