Abstract
BackgroundS100A4, a member of the calcium-binding proteins, is dramatically elevated in a variety of fibrotic diseases. Areca quid chewing is the most important etiological factor in the pathogenesis of oral submucous fibrosis (OSF). OSF has been considered as a pre-cancerous condition of oral mucosa. The aim of this study was to determine the critical role of S100A4 expression in the pathogenesis of OSF both in vitro and in vivo.Methodology/Principal FindingThirty OSF tissues from areca quid chewers and ten normal buccal mucosa samples without areca quid chewing were analyzed by using immunohistochemistry for S100A4 expression in vivo. Collagen gel contraction capability and expression of tissue inhibitor of metalloproteinases 1 (TIMP1)/MMP9 in arecoline-stimulated BMFs with S100A4 knockdown was presented in vitro. Initially, S100A4 expression was higher in areca quid chewing-associated OSF specimens than normal buccal mucosa specimens (p = 0.001). Arecoline, a major areca nut alkaloid, led to dose- and time-dependent elevation of S100A4 expression in normal buccal mucosa fibroblasts BMFs (p<0.05). The additions of pharmacological agents rapamycin (mTOR inhibitor), PD98059 (ERK inhibitor), and Bay117082 (NF-κB inhibitor) were found to inhibit arecoline-induced S100A4 expression (p<0.05) in BMFs. Down-regulation of S100A4 by lentiviral infection significantly reversed arecoline-induced collagen gel contraction and TIMP1/MMP9 expression.Conclusion/SignificanceThese results suggest that S100A4 expression is significantly up-regulated in OSF specimens. Arecoline-induced S100A4 expression was down-regulated by rapamycin, PD98059, and Bay117082. Targeting S100A4 might be a potential therapeutic target for OSF through TIMP1/MMP9 down-regulation.
Highlights
Oral submucous fibrosis (OSF) is a chronic progressive scarring disease which characterized by the submucosal accumulation of dense fibrous connective tissue with inflammatory cell infiltration and epithelial atrophy and has been considered as a pre-cancerous condition of oral mucosa [1]
Up-regulation of vimentin [5], cyclooxygenase-2 [6], tissue inhibitor metalloproteinase-1 (TIMP1) [7], plasminogen activator inhibitor-1 [8], interleukin-6 [9], keratinocyte growth factor-1 [10], insulin-like growth factor-1, nuclear factor-kappa B (NF-kB) [11], cystatin C [12], and heme oxygenase-1 [13] may contribute to the extracellular matrix (ECM) accumulation in oral submucous fibrosis (OSF)
To further study the possible mechanisms involved in arecolineinduced S100A4 up-regulation, we showed that arecoline treatment increased NF-kB, extracellular signal-regulated protein kinase (ERK), or mTOR signaling in buccal mucosa fibroblasts (BMFs) cells (Fig. 3A)
Summary
Oral submucous fibrosis (OSF) is a chronic progressive scarring disease which characterized by the submucosal accumulation of dense fibrous connective tissue with inflammatory cell infiltration and epithelial atrophy and has been considered as a pre-cancerous condition of oral mucosa [1]. A number of epidemiological evidences, case-series reports, large sized cross sectional surveys, case-control studies, cohort and intervention studies provide over whelming evidences that areca quid chewing is the main etiological factor for the development of OSF [3]. Areca quid chewing is the most important etiological factor in the pathogenesis of oral submucous fibrosis (OSF). OSF has been considered as a pre-cancerous condition of oral mucosa. The aim of this study was to determine the critical role of S100A4 expression in the pathogenesis of OSF both in vitro and in vivo
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