[HTML][HTML] A role of myocardin related transcription factor-A (MRTF-A) in scleroderma related fibrosis
X Shiwen, R Stratton, J Nikitorowicz-Buniak… - PloS one, 2015 - journals.plos.org
X Shiwen, R Stratton, J Nikitorowicz-Buniak, B Ahmed-Abdi, M Ponticos, C Denton…
PloS one, 2015•journals.plos.orgIn 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 …
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 …
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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