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Open Access Research article

Versican is upregulated in circulating monocytes in patients with systemic sclerosis and amplifies a CCL2-mediated pathogenic loop

Ayako Masuda1, Hidekata Yasuoka1, Takashi Satoh1, Yuka Okazaki1, Yukie Yamaguchi12 and Masataka Kuwana1*

Author Affiliations

1 Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shunjuku, Tokyo 160-8582, Japan

2 Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa 236-0004, Japan

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Arthritis Research & Therapy 2013, 15:R74  doi:10.1186/ar4251

Published: 11 July 2013

Abstract

Introduction

Altered phenotypes of circulating monocytes of patients with systemic sclerosis (SSc) have been reported, but the role of these alterations in the pathogenesis of SSc remains unclear. This study was undertaken to identify molecules that are preferentially expressed by SSc monocytes, and to investigate the roles of these molecules in the pathogenic process of SSc.

Methods

We analyzed circulating CD14+ monocytes isolated from 36 patients with SSc and 32 healthy control subjects. The monocytes' gene expression profiles were assessed by Oligo GEArray® (SABiosciences, Frederic, MA, USA) and semiquantitative or quantitative PCR; their protein expression was evaluated in culture supernatants of unstimulated monocytes by immunoblotting or ELISA, and by immunocytostaining. Monocyte chemoattractant activity of CCL2 was assessed in a TransWell® system (Corning Incorporated, Corning, NY, USA) in the presence or absence of chondroitin sulfate (CS).

Results

A step-wise approach to profiling gene expression identified that versican and CCL2 were upregulated in SSc monocytes. Subsequent analysis of proteins expressed in monocyte culture supernatants confirmed enhanced production of versican and CCL2 in SSc monocytes compared with control monocytes. CCL2 bound to CS chains of versican and colocalized with versican in the monocytes' Golgi apparatus. Finally, CCL2 had a greater ability to mediate monocyte migration when bound to CS chains, because this binding provided efficient formation of CCL2 gradients and protection from protease attack.

Conclusion

Circulating monocytes with elevated versican and CCL2 levels may contribute to the fibrotic process in a subset of SSc patients by amplifying a positive feedback loop consisting of versican, CCL2, and the influx of monocytes.

Keywords:
systemic sclerosis; monocytes; versican; CCL2