Clinical Correlations of Potential Activity Markers in Systemic Sclerosis

Bečvář, Radim; Štork, Jiří; Pešáková, V.; Stanova, Aliya K.; Hulejová, Hana; Rysová, L.; Zatloukalová, A.; Zatloukal, Petr; Jáchymová, M; Pourová, L.

doi:10.1196/annals.1361.082

Cited by 15 publications

(1 citation statement)

References 12 publications

(10 reference statements)

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“…MRTF-A in endothelial cells activates the adhesion molecule intercellular adhesion molecule 1, (ICAM-1), and endothelin through the inflammatory molecule nuclear factor kappa B (NFκB) subunit p65 and epigenetic modulating enzymes [ 55 , 56 ]. Both these MRTF-A targets are increased [ 57 ] and function in SSc [ 58 , 59 ]. MRTF-A also mediates TGFβ-induced endothelial to mesenchymal transition [ 30 ] which is important in SSc [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

Stratton

Nikitorowicz-Buniak

et al. 2015

PLoS ONE

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In scleroderma (systemic sclerosis, SSc), persistent activation of myofibroblast leads to severe skin and organ fibrosis resistant to therapy. Increased mechanical stiffness in the involved fibrotic tissues is a hallmark clinical feature and a cause of disabling symptoms. Myocardin Related Transcription Factor-A (MRTF-A) is a transcriptional co-activator that is sequestered in the cytoplasm and translocates to the nucleus under mechanical stress or growth factor stimulation. Our objective was to determine if MRTF-A is activated in the disease microenvironment to produce more extracellular matrix in progressive SSc. Immunohistochemistry studies demonstrate that nuclear translocation of MRTF-A in scleroderma tissues occurs in keratinocytes, endothelial cells, infiltrating inflammatory cells, and dermal fibroblasts, consistent with enhanced signaling in multiple cell lineages exposed to the stiff extracellular matrix. Inhibition of MRTF-A nuclear translocation or knockdown of MRTF-A synthesis abolishes the SSc myofibroblast enhanced basal contractility and synthesis of type I collagen and inhibits the matricellular profibrotic protein, connective tissue growth factor (CCN2/CTGF). In MRTF-A null mice, basal skin and lung stiffness was abnormally reduced and associated with altered fibrillar collagen. MRTF-A has a role in SSc fibrosis acting as a central regulator linking mechanical cues to adverse remodeling of the extracellular matrix.

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Section: Resultsmentioning

confidence: 99%

A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

Stratton

Nikitorowicz-Buniak

et al. 2015

PLoS ONE

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Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma

Duan

Fleming

Pritchard

et al. 2008

Arthritis & Rheumatism

125

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Objective. We attempted to elucidate possible pathogenetic mechanisms in scleroderma by analysis of gene expression patterns of purified monocytes and lymphocytes, as well as protein profiles of cytokines and growth factors.Methods. Expression analysis was performed on messenger RNA (mRNA) from cells that had been purified with magnetic beads. Plasma samples from the same patients were used for multiplex cytokine analysis. Potential sources of proteins were also examined by in situ hybridization of skin specimens.Results. A total of 1,800 genes from monocytes and 863 genes from CD4؉ T cells were differentially expressed in scleroderma patients. As observed by other investigators using unfractionated peripheral blood cells from patients with autoimmune connective tissue diseases, the cell type-specific analyses of our scleroderma samples showed expression of genes suggesting the presence of interferon-␣ (IFN␣), despite the apparent absence of this cytokine in plasma. IFN␣ RNA was, however, expressed at enhanced levels in vascular and perivascular cells in scleroderma skin samples. While levels of interleukin-1␣ (IL-1␣) and IL-16 were among 10 proteins found to be significantly elevated in scleroderma patients, none of the large panel of plasma cytokines we analyzed correlated with the expression levels of putative IFN response genes.Conclusion. The pattern of up-regulation of mRNA in both the monocytes and CD4 lymphocytes of scleroderma patients, together with the detection of IFN␣ RNA in the microvasculature, suggests that leukocytes respond to this cytokine locally in the vessels. Detection of high levels of IL-1␣ and IL-16 in plasma and the independence of these protein levels from the IFN signature, implicates an independent contribution of other cytokines to immune activation and/or inflammation in scleroderma.

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Biomarkers of Fibrosis

Beyer

Distler

2011

Scleroderma

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Clinical Correlations of Potential Activity Markers in Systemic Sclerosis

Cited by 15 publications

References 12 publications

A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma

Biomarkers of Fibrosis

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