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Abstract Number: 938

A Disintegrin and Metalloprotease-17 (ADAM-17) Is Expressed In Rheumatoid Arthritis and Mediates Monocyte Migration

Takeo Isozaki1, Nao Oguro2, Shinya Seki1, Yoko Miura1, Sho Ishii1, Hiroyuki Tsukamoto1, Takahiro Tokunaga1, Masayu Umemura1, Hidekazu Furuya1, Ryo Yanai1, Sakiko Isojima1, Kuninobu Wakabayashi1, Nobuyuki Yajima1, Yusuke Miwa1 and Tsuyoshi Kasama1, 1Div of Rheumatology, Showa University School of Med, Shinagawa-ku Tokyo, Japan, 2Div of Rhemuatology, Showa University School of Med, Shinagawa-ku Tokyo, Japan

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Inflammation, monocytes, Rheumatoid arthritis (RA), synovial cells, synovial fluid and tocilizumab

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Session Information

Session Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized byinflammation and joint destruction. Migration of monocytes/macrophages into the synovium is important in a variety of vasculoproliferatine states in RA. A disintegrin and metalloprotease (ADAM) are a family of proteases that are responsible for the liberation of a variety of types of cell surface expressed proteins.ADAM-17 has been shown to cleave a number of inflammatory mediators from the cell surface including CX3CL1 and CXCL16. In this study, we examined the expression of ADAM-17 in RA and the role it plays ininflammation.

Methods: ADAM-17 expression was determined in serumand synovial fluids from normal (NL) subjects, osteoarthritis (OA) patients and RA patients using enzyme linked immunosorbent assay. We also measured ADAM-17 in RA serum after treatment with tocilizmab (6, 12 and 24 week). To determine whether ADAM17 was expressed by THP-1 cells (human acute monocytic leukemia cell line)and whether it was regulated byphorbol 12-myristate 13-acetate (PMA), quantitative polymerase chain reaction (qPCR) was performed. In order to confirm the role of ADAM-17 in inflammation, we did THP-1 chemotaxis assay. To block the expression of ADAM-17, THP-1cells were transfected with siRNA against ADAM-17. After treatment with ADAM-17 siRNA, THP-1cell chemotaxis assay wasperformed towards RA synovial fluids and monocyte chemotactic protein-1 (MCP-1)/CCL2.

Results: ADAM-17 in RA serum (n=23) was significantly higher than NL serum (n=7)  (mean ± SEM RA serum 2093 ± 538 pg/ml and NL serum 0 ± 0pg/ml). ADAM-17 in RA synovial fluids (n=10) was also significantly higher than OA synovial fluids (n=7) (mean ± SEM RA synovial fluids 1645 ± 952 pg/ml and OA synovial fluids 5±4 pg/ml). After treatment with tocilizmab, ADAM-17 in serum was significantly decreased [pre 486 ± 126pg/ml (n=21), 12 week 215 ± 114 (n=15) and 24 week 98 ± 98 (n=12); p<0.05 between pre and 12 week, pre and 24 week]. The expression of ADAM-17 messenger RNA (mRNA) in THP-1 cells was induced by stimulation withPMA after 1 hour (2.6 fold increased). ADAM-17 siRNA treated THP-1 cells had decreased migration compared with control siRNA treated THP-1 cells towards RA synovial fluids (6± 2number of cells migrated and 33 ± 12 number of cells migrated, p<0.05). ADAM-17 siRNA treated THP-1 cells had also decreased migration compared with control siRNA treated THP-1 cells towards MCP-1/CCL2 (27 ± 4 number of cells migrated and 146 ± 18 number of cells migrated, p<0.05).

Conclusion: These data show that ADAM-17 is overexpressed in RA, and is decreased after treatment.ADAM-17 is involved monocyte migration, and this study suggests that ADAM-17 may play a role in RA inflammation. ADAM-17 may be a potential target in inflammatory disease like RA.


Disclosure:

T. Isozaki,
None;

N. Oguro,
None;

S. Seki,
None;

Y. Miura,
None;

S. Ishii,
None;

H. Tsukamoto,
None;

T. Tokunaga,
None;

M. Umemura,
None;

H. Furuya,
None;

R. Yanai,
None;

S. Isojima,
None;

K. Wakabayashi,
None;

N. Yajima,
None;

Y. Miwa,
None;

T. Kasama,
None.

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