{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T23:38:29Z","timestamp":1770680309906,"version":"3.49.0"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,3,30]],"date-time":"2009-03-30T00:00:00Z","timestamp":1238371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:p><jats:bold>Background and Objective:\u2002<\/jats:bold> Oral submucous fibrosis, a disease of collagen disorder, has been attributed to arecoline present in the saliva of betel quid chewers. However, the molecular basis of the action of arecoline in the pathogenesis of oral submucous fibrosis is poorly understood. The basic aim of our study was to elucidate the mechanism underlying the action of arecoline on the expression of genes in oral fibroblasts.<\/jats:p><jats:p><jats:bold>Material and Methods:\u2002<\/jats:bold> Human keratinocytes (HaCaT cells) and primary human gingival fibroblasts were treated with arecoline in combination with various pathway inhibitors, and the expression of transforming growth factor\u2010beta isoform genes and of collagen isoforms was assessed using reverse transcription\u2013polymerase chain reaction analysis.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> We observed the induction of transforming growth factor\u2010beta2 by arecoline in HaCaT cells and this induction was found to be caused by activation of the M\u20103 muscarinic acid receptor via the induction of calcium and the protein kinase C pathway. Most importantly, we showed that transforming growth factor\u2010beta2 was significantly overexpressed in oral submucous fibrosis tissues (<jats:italic>p<\/jats:italic>\u2003=\u20030.008), with a median of 2.13 (<jats:italic>n<\/jats:italic>\u2003=\u200321) compared with 0.75 (<jats:italic>n<\/jats:italic>\u2003=\u200318) in normal buccal mucosal tissues. Furthermore, arecoline down\u2010regulated the expression of collagens 1A1 and 3A1 in human primary gingival fibroblasts; however these collagens were induced by arecoline in the presence of spent medium of cultured human keratinocytes. Treatment with a transforming growth factor\u2010beta blocker, transforming growth factor\u2010beta1 latency\u2010associated peptide, reversed this up\u2010regulation of collagen, suggesting a role for profibrotic cytokines, such as transforming growth factor\u2010beta, in the induction of collagens.<\/jats:p><jats:p><jats:bold>Conclusion:\u00a0<\/jats:bold> Taken together, our data highlight the importance of arecolineinduced epithelial changes in the pathogenesis of oral submucous fibrosis.<\/jats:p>","DOI":"10.1111\/j.1600-0765.2008.01185.x","type":"journal-article","created":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T03:21:40Z","timestamp":1238469700000},"page":"736-743","source":"Crossref","is-referenced-by-count":20,"title":["Regulation of extracellular matrix genes by arecoline in primary gingival fibroblasts requires epithelial factors"],"prefix":"10.1111","volume":"44","author":[{"given":"G. 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