{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:40:28Z","timestamp":1790836828509,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2009,10,29]],"date-time":"2009-10-29T00:00:00Z","timestamp":1256774400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2009,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor \u03b2 (TGF\u03b2) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGF\u03b2\/Smad signaling through the activation of nuclear translocation of Y\u2010box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGF\u03b2, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg\/kg\/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin\u2010induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pretreatment with HSc025 prevented Smad\u2010dependent promoter activation, in a dose\u2010dependent manner; however, HSc025 had no effect on TGF\u03b2\u2010induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGF\u03b2\u2010induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin\u2010treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate that HSc025 is a novel inhibitor of TGF\u03b2\/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.24934","type":"journal-article","created":{"date-parts":[[2009,10,29]],"date-time":"2009-10-29T21:16:37Z","timestamp":1256850997000},"page":"3465-3475","source":"Crossref","is-referenced-by-count":48,"title":["A novel inhibitor of Smad\u2010dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic 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