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In this study, we explored the role of LIM and cysteine\u2010rich domains protein 1 (LMCD1) as a novel factor in the pathogenesis of SSc\u2010related ILD (SSc\u2010ILD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression and effects of LMCD1 were studied in lung tissue samples and fibroblasts from SSc\u2010ILD patients and control subjects as well as in lung tissue samples from animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LMCD1 was consistently elevated in lung tissue samples and in fibroblasts isolated from SSc\u2010ILD patients as compared to controls. Additionally, LMCD1 was found to be highly expressed in the lung in the fibroblast\u2010specific protein (FSP)\u2013driven, constitutively active transforming growth factor \u03b2 receptor type I (TGF\u03b2R1) transgenic mouse model of ILD and the bleomycin\u2010induced mouse model of ILD. In lung fibroblasts from SSc\u2010ILD patients, LMCD1 is an essential factor for the TGF\u03b2\u2010induced generation of type I collagen, fibronectin, and \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA). Depletion of LMCD1 by small interfering RNA reduced the expression of extracellular matrix proteins and lowered transcriptional activity and expression of \u03b1\u2010SMA, as well as decreased the proliferation and contractile activity of SSc\u2010ILD lung fibroblasts. In dense fibrotic areas of affected lung tissue, lung LMCD1 colocalized with \u03b1\u2010SMA. In cultured scleroderma lung fibroblasts, LMCD1 colocalized and interacted with serum response factor which mediates LMCD1\u2010induced contractile activity of lung fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study identifies LMCD1 as a profibrotic molecule contributing to the activation of myofibroblasts and the persistent fibroproliferation observed in SSc\u2010ILD. Thus, LMCD1 may be a potential novel therapeutic target for patients with SSc\u2010ILD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42344","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T13:19:49Z","timestamp":1663161589000},"page":"438-448","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Critical Role of <scp>LMCD1<\/scp> in Promoting Profibrotic Characteristics of Lung Myofibroblasts in Experimental and Scleroderma\u2010Associated Lung Fibrosis"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-1586","authenticated-orcid":false,"given":"Galina S.","family":"Bogatkevich","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology, Department of Medicine Medical University of South Carolina  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