Research article

Expression of ADAM15 in rheumatoid synovium: up-regulation by vascular endothelial growth factor and possible implications for angiogenesis

Koichiro Komiya^1,2, Hiroyuki Enomoto², Isao Inoki¹, Satoko Okazaki¹, Yoshinari Fujita^1,2, Eiji Ikeda¹, Eiko Ohuchi³, Hideo Matsumoto², Yoshiaki Toyama² and Yasunori Okada^1*

• * Corresponding author: Yasunori Okada okada@sc.itc.keio.ac.jp

Author Affiliations

¹ Department of Pathology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

² Department of Orthopaedic Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

³ Biopharmaceutical Department, Daiichi Fine Chemical Co. Ltd., Takaoka, Toyama, Japan

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Arthritis Research & Therapy 2005, 7:R1158-R1173 doi:10.1186/ar1796

Published: 5 August 2005

Abstract

ADAMs (a disintegrin and metalloproteinases) comprise a new gene family of metalloproteinases, and may play roles in cell-cell interaction, cell migration, signal transduction, shedding of membrane-anchored proteins and degradation of extracellular matrix. We screened the mRNA expression of 10 different ADAMs with a putative metalloproteinase motif in synovial tissues from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Reverse transcription PCR and real-time quantitative PCR analyses indicated that among the ADAMs, ADAM15 mRNA was more frequently expressed in the RA samples and its expression level was significantly 3.8-fold higher in RA than in OA (p < 0.01). In situ hybridization, immunohistochemistry and immunoblotting demonstrated that ADAM15 is expressed in active and precursor forms in the synovial lining cells, endothelial cells of blood vessels and macrophage-like cells in the sublining layer of RA synovium. There was a direct correlation between ADAM15 mRNA expression levels and vascular density in the synovial tissues (r = 0.907, p < 0.001; n = 20). ADAM15 was constitutively expressed in RA synovial fibroblasts and human umbilical vein endothelial cells (HUVECs), and the expression level was increased in HUVECs by treatment with vascular endothelial growth factor (VEGF)₁₆₅. On the other hand, ADAM15 expression in RA synovial fibroblasts was enhanced with VEGF₁₆₅ only if vascular endothelial growth factor receptor (VEGFR)-2 expression was induced by treatment with tumor necrosis factor-α, and the expression was blocked with SU1498, a specific inhibitor of VEGFR-2. These data demonstrate that ADAM15 is overexpressed in RA synovium and its expression is up-regulated by the action of VEGF₁₆₅ through VEGFR-2, and suggest the possibility that ADAM15 is involved in angiogenesis in RA synovium.