title: A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis.
abstract: 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.
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Xu
authors.initials: X
authors.lastname: Shiwen
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Stratton
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Nikitorowicz-Buniak
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Bahja
authors.initials: B
authors.lastname: Ahmed-Abdi
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Markella
authors.initials: M
authors.lastname: Ponticos
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Denton
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Campus, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Abraham
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Bela
authors.initials: B
authors.lastname: Suki
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Layne
authors.affiliation: Rheumatology Department, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000818:Animals; D019070:Cell Lineage; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D012595:Scleroderma, Systemic / Q000235:genetics*; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; C431575:MRTFA protein, human; D015534:Trans-Activators; D055513:Connective Tissue Growth Factor