Arthritis Rheum. 2013 May;65(5):1378-83.

CD109 overexpression ameliorates skin fibrosis in a mouse model of bleomycin-induced scleroderma.

Vorstenbosch J, Al-Ajmi H, Winocour S, Trzeciak A, Lessard L, Philip A.

Division of Plastic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada.

 

Abstract

OBJECTIVE:

Transforming growth factor β (TGFβ) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGFβ signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGFβ coreceptor and have shown that it antagonizes TGFβ signaling and TGFβ-induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin-induced SSc.

METHODS:

Transgenic mice overexpressing CD109 in the epidermis and their wild-type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Masson’s trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGFβ signaling was examined by determining phospho-Smad2 and phospho-Smad3 levels using Western blotting and immunohistochemistry.

RESULTS:

Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycin-induced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels, as compared to their WT littermates.

CONCLUSION:

Our findings suggest that CD109 inhibits TGFβ signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal-epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma.

Copyright © 2013 by the American College of Rheumatology.

PMID: 23436317

 

Supplementary information

Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine that plays critical roles in normal development and tissue homeostasis by regulating a multitude of cellular processes including proliferation, differentiation and extracellular matrix (ECM) production. Aberrant TGF-β signaling has been implicated in several human diseases including ‘fibro-proliferative’ disorders such as hypertrophic scarring and scleroderma. Identification of novel proteins that modulate TGF-β signaling may allow the manipulation of TGF-β action to control scarring and fibrosis.  We have identified CD109, a cell-surface glycosylphosphatidylinositol (GPI)-anchored protein, as a TGF-β co-receptor that binds TGF-β with high affinity and inhibits TGF-β signaling and responses in human skin cells in vitro[1]. To understand the role of CD109 in vivo, we generated transgenic mice that express CD109 under the K14 promoter to restrict transgene expression to the epidermis. Our results indicate that CD109 transgenic mice display decreased inflammation and granulation tissue and improved collagen architecture during wound healing[2] and a resistance to bleomycin-induced skin fibrosis[3]. In addition, we showed that blocking CD109 expression increased and addition of  CD109 protein decreased TGF-β-induced pro-fibrotic responses in scleroderma and normal human skin cells[4]. Taken together, our results indicate that CD109 displays anti-fibrotic effects in vitro and in vivo, and suggest that CD109 may represent a novel molecular target for the development of anti-fibrotic therapy. A schematic diagram showing how CD109 inhibits TGF-β signaling to reduce fibrosis is illustrated in Figure 1.

Kenneth Finnson-1

Figure 1. Schematic diagram depicting how CD109 acts to inhibit TGF-β signaling and profibrotic-responses (type I collagen and fibronectin expression) which is expected to reduced fibrosis in skin (and other) tissue.

 

REFERENCES

1.         Finnson KW, Tam BY, Liu K, Marcoux A, Lepage P, Roy S, Bizet AA, Philip A: Identification of CD109 as part of the TGF-β receptor system in human keratinocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006, 20(9):1525-1527.

2.         Vorstenbosch J, Gallant-Behm C, Trzeciak A, Roy S, Mustoe T, Philip A: Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 2013, 21(2):235-246.

3.         Vorstenbosch J, Al-Ajmi H, Winocour S, Trzeciak A, Lessard L, Philip A: CD109 overexpression ameliorates skin fibrosis in a bleomycin-induced mouse model of scleroderma. Arthritis and rheumatism 2013, 65(5):1378-1383.

4.         Man XY, Finnson KW, Baron M, Philip A: CD109, a TGF-β co-receptor, attenuates extracellular matrix production in scleroderma skin fibroblasts. Arthritis research & therapy 2012, 14(3):R144.

 

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