Proteomic analysis of scleroderma lesional skin reveals activated wound healing phenotype of epidermal cell layer

Aden, N; Xu, Shiwen; Aden, Durre; Black, Carol M.; Nuttall, Anna; Denton, Christopher P.; Leask, Andrew; Abraham, David; Stratton, Richard

doi:10.1093/rheumatology/ken370

Cited by 81 publications

(63 citation statements)

References 42 publications

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“…In some diseased states such as in psoriasis where the epithelial cells undergo hyperproliferation and/or aberrant differentiation, expression of keratins K6 and its partner K16 are induced in the inter-follicular epidermis (Bernot et al, 2002). Recent, proteomic analysis of whole skin lesions from SSc patients shows abnormal expression of K6 and K16 suggesting hyperproliferation of the epidermal component in SSc (Aden et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Sonnylal

Jones

et al. 2013

Journal of Cell Science

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SummaryConnective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for aSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells coexpressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFb, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of a-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.

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Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Sonnylal

Jones

et al. 2013

Journal of Cell Science

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“…Of interest, immunohistochemical validation of these data showed that the cells responsible for the increased gene expression are keratinocytes from the basal layer of the epidermis, presenting a new and challenging concept in SSc pathophysiology. Indeed, the notion of epithelial cells playing a crucial role in the pathogenesis of skin fibrosis was more recently confirmed by another elegant proteomic study on SSc skin biopsies [18]. In fact, Aden et al [18] have shown convincing data indicating that the epithelial cells in SSc are activated and express a wound healing-like phenotype.…”

Section: Gene Expression Profiling and Molecular Subsets In Systemic mentioning

confidence: 96%

“…Indeed, the notion of epithelial cells playing a crucial role in the pathogenesis of skin fibrosis was more recently confirmed by another elegant proteomic study on SSc skin biopsies [18]. In fact, Aden et al [18] have shown convincing data indicating that the epithelial cells in SSc are activated and express a wound healing-like phenotype.…”

Section: Gene Expression Profiling and Molecular Subsets In Systemic mentioning

confidence: 96%

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Biomarkers in the Management of Scleroderma: An Update

et al. 2010

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Scleroderma, or systemic sclerosis, is a clinically heterogeneous disease characterized by fibroproliferative vasculopathy, tissue fibrosis affecting the skin and internal organs, and autoimmune activation. Many biomarker candidates have been identified in the past two decades; however, fully validated measures are still lacking with regard to aiding in the early diagnosis and reflecting the disease activity, severity, prognosis, and response to therapy. An ideal biomarker should be highly sensitive and specific, reflecting the current status of disease; should be related to the disease activity and/or severity in accordance with the clinical evolution; should anticipate clinical changes before they occur; and should add independent information about the risk or prognosis that is reproducible and feasible. This review focuses on the most recent and innovative approaches to identify biomarkers, such as extensive gene expression analysis and proteomics, and on markers and surrogate outcome measures closer to clinical practice, and attempts to evaluate them through the OMERACT (Outcome Measures in Rheumatology Clinical Trials) filter.

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“…Some of the same barriers to effective application of mass spectrometry as an analytical tool (as discussed above) have impeded analysis of cell-cell and cell-matrix adhesion-dependent processes such as wound healing and cancer (14). The study of extracellular matrix (ECM) 1 and adhesion-related proteins is further complicated by the difficulty in sample preparation because compared with cytosolic proteins basal cell proteins are often highly insoluble (e.g.…”

mentioning

confidence: 99%

Detection of Differentially Expressed Basal Cell Proteins by Mass Spectrometry

Todorović

Desai

Eigenheer

et al. 2010

Molecular & Cellular Proteomics

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The ability of cells to modulate interactions with each other and the substrate is essential for epithelial tissue remodeling during processes such as wound healing and tumor progression. However, despite strides made in the field of proteomics, proteins involved in adhesion have been difficult to study. Here, we report a method for the enrichment and analysis of proteins associated with the basal surface of the cell and its underlying matrix. The enrichment involves deroofing the cells with 20 mM ammonium hydroxide and the removal of cytosolic and organellar proteins by stringent water wash. Proteomic profiling was achieved by LC-FTMS, which allowed comparison of differentially expressed or shared proteins under different cell states. First, we analyzed and compared the basal cell components of mouse keratinocytes lacking the cell-cell junction molecule plakoglobin with their control counterparts. Changes in the molecules involved in motility and invasion were detected in plakoglobin-deficient cells, including decreased detection of fibronectin, integrin ␤ 4 , and FAT tumor suppressor. Second, we assessed the differences in basal cell components between two human oral squamous cell carcinoma lines originating from different sites in the oral cavity (CAL33 and UM-SCC-1). The data show differences between the two lines in the type and abundance of proteins specific to cell adhesion, migration, and angiogenesis. Therefore, the method described here has the potential to serve as a platform to assess proteomic changes in basal cell components including extracellular and adhesion-specific proteins involved in wound healing, cancer, and chronic and acquired adhesion-related disorders. Molecular & Cellular Proteomics 9:351-361, 2010.

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Proteomic analysis of scleroderma lesional skin reveals activated wound healing phenotype of epidermal cell layer

Cited by 81 publications

References 42 publications

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Biomarkers in the Management of Scleroderma: An Update

Detection of Differentially Expressed Basal Cell Proteins by Mass Spectrometry

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