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

Division of Plastic Surgery, Department of Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal, H3G 1A4,Canada. .
Arthritis research & therapy (Impact Factor: 3.75). 06/2012; 14(3):R144. DOI: 10.1186/ar3877
Source: PubMed


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.
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.
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.
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.

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Available from: Anie Philip, Mar 12, 2014
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    • "It has been reported that CD109 is expressed on activated T lymphocytes and platelets, endothelial cells and a subpopulation of CD34+ hematopoietic stem and progenitor cells [20,21,41]. CD109 is also expressed in keratinocytes and contributes to the inhibition of extracellular matrix production in scleroderma [42]. In addition, it is also expressed in malignancies of the lung, esophagus, cervix, urinary tract and breast and plays a role in the tumor growth of oral cancer [43]. "
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    ABSTRACT: Epithelioid sarcoma (ES) is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX) and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs) based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDH(high) cells) correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDH(high) cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis (P = 0.009). In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.
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    • "Several studies have shown that human cells overexpressing CD109 exhibited enhanced proliferation compared with control cells and therefore this molecule is known to be involved in tumourigenesis [21]. In relation to this, it is known that the gene for CD109 is mutated in colorectal cancer [22] and its expression is altered in many other types of malignancies [20], [21], [23], [24], [25], [26], [27], [28] and even in psoriasis [29]. "
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    • "Further analysis of CD34+ cells in different products may explain the CD109 mRNA expression level as well. HF, which is also known to have CD109 protein expression [18, 19] showed very high expression of CD109 mRNA. In a previous study, the level of CD109 mRNA expression was compared with normal fibroblasts and scleroderma skin fibroblasts and showed no significant difference [19]. "
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