{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:06:06Z","timestamp":1791234366667,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,5,25]],"date-time":"2015-05-25T00:00:00Z","timestamp":1432512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Fondazione di Medicina Molecolare e Terapia Cellulare"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Reactive oxygen species (ROS) contribute to the pathogenesis of fibrosis in systemic sclerosis (SSc; scleroderma), and NADPH oxidase (NOX) is an important source of ROS. Since the role of single NOX isoforms has not been previously investigated in SSc, this study was undertaken to assess the expression of NOX in SSc fibroblasts compared to normal healthy cells and to analyze their role in cell activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of NOX isoforms in dermal fibroblasts from patients with SSc and healthy control subjects was analyzed by real\u2010time polymerase chain reaction, immunoblotting, and immunofluorescence. NOX isoforms were silenced using small interfering RNA. Production of ROS was measured by fluorometry and confocal microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Scleroderma fibroblasts showed up\u2010regulation of NOX\u20102 and NOX\u20104 protein and messenger RNA (mRNA) expression. Treatment of the cells with diphenyleneiodonium, a nonselective inhibitor of flavin\u2010containing enzymes, and silencing of NOX2 and NOX4 decreased the production of ROS as well as the expression of type I collagen and \u03b1\u2010smooth muscle actin in SSc fibroblasts. ROS generated by NOX\u20102 and NOX\u20104 were involved in DNA damage and activation of a DNA repair checkpoint. Incubation of healthy control fibroblasts with platelet\u2010derived growth factor (PDGF) or with IgG isolated from SSc patient serum enhanced the expression of NOX2 and NOX4 mRNA, via ROS, in a time\u2010dependent manner. Treatment with actinomycin D, a transcription inhibitor, reversed the effects of PDGF stimulation but not the effects of SSc IgG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Both NOX2 and NOX4 generate ROS in SSc fibroblasts and play a critical role in cell activation and DNA damage. Expression of NOX\u20102 and NOX\u20104 in SSc fibroblasts is maintained by a ROS\u2010mediated loop.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39084","type":"journal-article","created":{"date-parts":[[2015,2,23]],"date-time":"2015-02-23T11:20:07Z","timestamp":1424690407000},"page":"1611-1622","source":"Crossref","is-referenced-by-count":58,"title":["A Reactive Oxygen Species\u2013Mediated Loop Maintains Increased Expression of NADPH Oxidases 2 and 4 in Skin Fibroblasts From Patients With Systemic Sclerosis"],"prefix":"10.1002","volume":"67","author":[{"given":"Tatiana","family":"Spadoni","sequence":"first","affiliation":[{"name":"Universit\u00e0 Politecnica delle Marche Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Svegliati Baroni","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Politecnica delle Marche Ancona 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