CD109, a TGF-β co-receptor, attenuates extracellular matrix production in scleroderma skin fibroblasts

Xiao-Yong Man,Anie Philip,Murray Baron,Kenneth W Finnson

doi:10.1186/ar3877

Abstract

IntroductionScleroderma or systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of skin and internal organs. Transforming growth factor beta (TGF-β) plays a key role in the pathogenesis of SSc fibrosis. We have previously identified CD109 as a novel TGF-β co-receptor that inhibits TGF-β signaling. The aim of the present study was to determine the role of CD109 in regulating extracellular matrix (ECM) production in human SSc skin fibroblasts.MethodsCD109 expression was determined in skin tissue and cultured skin fibroblasts of SSc patients and normal healthy subjects, using immunofluorescence, western blot and RT-PCR. The effect of CD109 on ECM synthesis was determined by blocking CD109 expression using CD109-specific siRNA or addition of recombinant CD109 protein, and analyzing the expression of ECM components by western blot.ResultsThe expression of CD109 proteinis markedly increased in SSc skin tissue in vivo and in SSc skin fibroblasts in vitro as compared to their normal counterparts. Importantly, both SSc and normal skin fibroblasts transfected with CD109-specific siRNA display increased fibronectin, collagen type I and CCN2 protein levels and enhanced Smad2/3 phosphorylation compared with control siRNA transfectants. Furthermore, addition of recombinant CD109 protein decreases TGF-β1-induced fibronectin, collagen type I and CCN2 levels in SSc and normal fibroblasts.ConclusionThe upregulation of CD109 protein in SSc may represent an adaptation or consequence of aberrant TGF-β signaling in SSc. Our finding that CD109 is able to decrease excessive ECM production in SSc fibroblasts suggest that this molecule has potential therapeutic value for the treatment of SSc.

Highlights

Scleroderma or systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of skin and internal organs
The expression of CD109 proteinis markedly increased in SSc skin tissue in vivo and in SSc skin fibroblasts in vitro as compared to their normal counterparts. Both SSc and normal skin fibroblasts transfected with CD109-specific small interfering RNA (siRNA) display increased fibronectin, collagen type I and connective tissue growth factor (CCN2) protein levels and enhanced Smad2/3 phosphorylation compared with control siRNA transfectants
CD109 protein expression is increased in SSc skin compared with normal skin in vivo We have previously demonstrated that CD109 is expressed in vitro in normal human keratinocytes [37,39,40] and fibroblasts [41,42]

Summary

Introduction

Scleroderma or systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of skin and internal organs. Scleroderma or systemic sclerosis (SSc) is a complex connective tissue disorder characterized by autoimmunity, vasculopathy and progressive fibrosis of skin and internal organs [1,2,3]. Some studies have demonstrated increased TGF-b receptor levels in SSc fibroblasts [17,18,19] that might contribute to activation of autocrine TGF-b signaling [16]. These findings have not been universally reproduced [20,21], emphasizing the need for further investigation

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