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


CONCLUSIONS
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.
Division of Plastic Surgery, Department of Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal, H3G 1A4,Canada.
Xiao-Yong
XY
Man
Kenneth W
KW
Finnson
Murray
M
Baron
Anie
A
Philip
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; C120523:CD109 protein, human; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta