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Open Access Highly Accessed Research article

Adenosine A2A receptors promote collagen production by a Fli1- and CTGF-mediated mechanism

Edwin SL Chan1*, Hailing Liu1, Patricia Fernandez12, Alex Luna1, Miguel Perez-Aso1, Andreea M Bujor3, Maria Trojanowska3 and Bruce N Cronstein1

Author affiliations

1 Department of Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA

2 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA

3 Department of Medicine, Arthritis Center, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA

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Citation and License

Arthritis Research & Therapy 2013, 15:R58  doi:10.1186/ar4229

Published: 11 May 2013

Abstract

Introduction

Adenosine, acting through the A2A receptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models. Since expression of A2A receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2A receptor produces its fibrogenic effects.

Methods

The effects of A2A receptor ligation on the expression of the transcription factor, Fli1, a constitutive repressor for the synthesis of matrix proteins, such as collagen, is studied in dermal fibroblasts. Fli1 is also known to repress the transcription of CTGF/CCN2, and the effects of A2A receptor stimulation on CTGF and TGF-β1 expression are also examined.

Results

A2A receptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A2A receptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A2A receptor-mediated enhancement of collagen type I production. A2AR activation, however, resulted in a decrease in TGF-β1 protein release.

Conclusions

Our results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A2A receptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma.

Keywords:
Fibrosis; fibroblast; scleroderma