Tropisetron suppresses collagen synthesis in skin fibroblasts via α7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model. Issue 3 (25th February 2013)

• Record Type: Journal Article
• Authors: Stegemann, Agatha; Sindrilaru, Anca; Eckes, Beate; del Rey, Adriana; Heinick, Alexander; Schulte, Jan S.; Müller, Frank U.; Grando, Sergei A.; Fiebich, Bernd L.; Scharffetter‐Kochanek, Karin; Luger, Thomas A.; Böhm, Markus
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 3(2013:Mar.)
• Page Start: 792
• Page End: 804
• Publication Date: 2013-02-25
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37809
• Languages: English
• ISSNs: 0004-3591

Abstract

Abstract: Objective: There is increasing evidence that serotonin (5‐hydroxytryptamine [5‐HT]) and distinct 5‐HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5‐HT3/4 receptor–modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. Methods: Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca 2+ measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription–polymerase chain reaction (RT‐PCR) and immunofluorescence. The murine model of bleomycin‐induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real‐time RT‐PCR analysis, Western immunoblotting, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and immunohistochemical analysis. Results: Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5‐HT3/4 receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1‐induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c‐Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. Conclusion: Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR‐dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin‐ induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma.