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CD109, a TGF-β co-receptor, attenuates extracellular matrix production in scleroderma skin fibroblasts
Xiao-Yong Man1, Kenneth W Finnson, Murray Baron
1Division of Plastic Surgery, Department of Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal, H3G 1A4,Canada.
Introduction:
Scleroderma 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.
Methods:
CD109 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.
Results:
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. 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.
Conclusion:
The 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.
Insights
CD109 protein is upregulated in scleroderma (SSc) and inhibits extracellular matrix production. This suggests CD109 may be a therapeutic target for treating SSc fibrosis.
Area of Science:
- Immunology
- Dermatology
- Fibrosis Research
Background:
- Scleroderma (SSc) is a connective tissue disease causing fibrosis.
- Transforming growth factor beta (TGF-β) drives SSc fibrosis.
- CD109 acts as a TGF-β co-receptor inhibiting TGF-β signaling.
Purpose of the Study:
- Investigate CD109's role in regulating extracellular matrix (ECM) production.
- Determine CD109's function in human SSc skin fibroblasts.
Main Methods:
- Assessed CD109 expression in SSc and normal skin fibroblasts (immunofluorescence, western blot, RT-PCR).
- Manipulated CD109 levels using siRNA and recombinant protein.
- Analyzed ECM component and Smad2/3 phosphorylation levels.
Main Results:
- CD109 protein expression is significantly increased in SSc skin.
- Blocking CD109 increased ECM components (fibronectin, collagen type I, CCN2) and Smad2/3 phosphorylation.
- Recombinant CD109 protein reduced TGF-β1-induced ECM production.
Conclusions:
- Upregulated CD109 in SSc may be a response to aberrant TGF-β signaling.
- CD109 reduces excessive ECM production in SSc fibroblasts.
- CD109 shows potential as a therapeutic agent for SSc treatment.
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