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Objective: The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment strategies. The lack of suitable animal models is a major hindrance. Therefore, this study aimed to address this issue by comparing commonly used arecoline-induced water drinking and injection mouse models., Materials and Methods: The mice were subjected to two protocols: receiving 2 mg/mL arecoline in drinking water and 4 mg/mL arecoline saline solution injections every other day. Tissues were collected at regular 4-week intervals, with a final time point of 20 weeks. Stereo microscopy and histomorphological analysis were performed on live and harvested tissues, respectively., Results: During arecoline treatment, collagen deposition and myofibroblast proliferation progressively increased in both models. Changes in the collagen I/III ratio indicated that both models exhibited characteristics of the early and intermediate stages of OSF after 20 weeks of arecoline induction. The water-drinking model also demonstrated multi-organ fibrosis involving the tongue, lungs, and small intestine., Conclusion: Both the water drinking and injection mouse models effectively induced OSF, but the water-drinking model better mirrored the observed pathogenesis in patients with OSF. These models provide valuable tools for investigating the mechanisms underlying OSF., (© 2023 Wiley Periodicals LLC.)

Objectives: An umbrella review is a systematic review of systematic reviews, which provides a tertiary level of evidence. This umbrella review of systematic reviews and meta-analysis (SR-MA) aimed to determine the proportion of oral cancer (OC) development in oral submucous fibrosis (OSF) patients., Materials and Methods: We searched electronic databases including PubMed, Scopus, Web of Science, Cochrane and grey literature. Two reviewers independently screened abstracts and assessed for eligible papers. The methodological quality of SR-MA was evaluated using AMSTAR2, and we also checked the quality of evidence of the included papers., Results: Out of 454 papers identified in the primary search, 105 underwent eligibility screening. Inclusion criteria were met by four SR-MA. OC ratios ranged between 4.2% and 6% for OSF. Substantial heterogeneity was observed for this outcome in all four MA (I 2  = 71.31% to 86.37%). None of the SRs assessed the quality of evidence, and half of them were judged to be of critically low methodological quality., Conclusion: There is lack of quality of evidences and critically low methodological quality among SRs and MA leading to substantial heterogeneity. However, due to potentially malignant nature, OSF patients should be monitored carefully for early detection of OC., (© 2023 Wiley Periodicals LLC.)

Objectives: Fibroblast activating protein (FAP) is associated with various organ fibrosis. However, the expression and molecular function of FAP in oral submucous fibrosis (OSF) is still unclear., Materials and Methods: The high-performance liquid chromatography was used to detect the presence of alkaloids in areca nut extract (ANE). Real-time qPCR, Western blot, and Immunohistochemistry assay were used to analyze the expression of FAP mRNA or protein in OSF and normal oral tissue. A chi-squared test analyzed the relationship between FAP protein expression and clinicopathological data of OSF patients. CCK-8, Wound-healing, and Transwell migration assay were employed to assess the effect of the proliferation and migration ability of hOMF cells with FAP overexpression or knockdown. The expression level of a-SMA, FSP1, and P13K-Akt signaling pathways-related protein in hOMF cells transfected with FAP overexpression or knockdown plasmid was verified by western blot assay., Results: The four specific areca alkaloids (Arecoline, Guvacine, Arecaidine, and Guvacoline) were successfully detected in the ANE. The viability of hOMF cells was significantly improved in the 50 μg/mL ANE group and was inhibited in the 5 and 50 mg/mL ANE groups. The expression of FAP was upregulated in OSF tissues, and hOMF cells treated with 50 μg/mL ANE and was related to pathology grade, clinical stage, and history of chewing betel nut. Additionally, FAP may promote the proliferation, migration, and activation of hOMF cells through the P13K-Akt signaling pathway., Conclusions: This study found that ANE had a bidirectional effect on the viability of hOMF cells, and the FAP gene was a potential therapeutic target in OSF., (© 2023 Wiley Periodicals LLC.)

Objective: Oral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease, we hypothesized that there would be extensive epigenetic changes in OSF tissues., Materials and Methods: Using the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses was conducted to find commonly regulated genes., Results: A total of 3,294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated-hypermethylated genes and 55 hypomethylated-upregulated genes. Using methylation-specific and qRT-PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3, and ACSL4 genes were confirmed. Pathways involved in insulin signaling, ubiquitin-mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter., Conclusions: This study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF., (© 2021 Wiley Periodicals LLC.)

Objectives: Fibrosis diseases are one of the leading causes of suffering and death. However, no systematic investigation has been carried out on fibrosis-related genes., Materials and Methods: By querying PubMed using keywords "fibrosis" and "gene" or "protein," we identified fibrosis-related genes in the last decade. Bioinformatics analysis was performed by MAS 3.0 software. Key miRNA was selected to assess its relationship with oral submucous fibrosis (OSF) and fibroblast functions., Results: A total of 1,310 genes related to fibrosis were identified. TGF-β1, CTGF, MMP9, HSP47, and S1P were found to be associated with mainly fibrotic organs. In total, 244 cellular components terms, 595 molecular function terms, 1,816 cellular component terms, and 136 KEGG pathway annotations were predicted. miR-199-5p was selected as the key miRNA, which has higher level in OSF. Upregulated miR-199-5p was significantly related to OSF duration and OSF histological grade (p = 0.028 and 0.012, respectively). Overexpressive miR-199-5p reduced proliferation and induced apoptosis in buccal fibroblasts. Additionally, expression levels of collagen I (COL I) and III (COL III) were promoted by overexpressive miR-199-5p in buccal fibroblasts., Conclusion: These results indicate that fibrosis-related genes are related to a series of complex mechanisms. The characteristics of miR-199-5p may supply important clues for developing therapeutic strategy for OSF., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

In oral cancer, acquisition of α-smooth muscle actin (α-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important event for progression and metastasis. However, the contribution of myofibroblasts in oral potentially malignant disorders (OPMD) remains controversial. This systematic review provides evidence that immunodetection of myofibroblasts may identify oral submucous fibrosis (OSMF) with high risk of malignant transformation, but does not represent an auxiliary tool to predict the malignant potential of leukoplakia and erythroplakia, the most common OPMD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objective: Patients with oral submucous fibrosis (OSF) suffer from the limitation of the oral opening. The aim of this study was to develop a simple and rapid method to improve the opening of the oral cavity and determine its effect on the incidence of developing oral carcinoma., Methods: We first induced an OSF-like lesion in rabbits which histopathologically resembles OSF in betel nut chewers and evaluated the effects of exogenous collagenase on these lesions. We then applied the collagenase treatment regimen to patients with OSF., Results: Endogenous collagenase activities in normal oral mucosa of patients exhibited 3- to 5-fold higher levels than that of OSF tissues. The collagenase treatment not only resulted in a significant improvement of oral opening, but patients also experienced a striking reduction in hypersensitivity to spices, sour, cold, and heat which helped restore eating function. Sub-mucosal fibrous proliferation, persistently good vascularization, and a mild increase in thickness of the sub-mucosal fibrous tissues were noticed 10 months after collagenase treatment. Within the 2-year follow-up period none of the treated patients developed an oral squamous cell carcinoma., Conclusion: A reduced content of functional collagenase observed in OSF mucosa of patients might be one mechanism responsible for collagen accumulation. Intervention of OSF by collagenase treatment at the early stage may reduce the incidence of developing oral carcinoma.

Objective: Plasminogen activators and their inhibitors are thought to be key participants in the balance of proteolytic and antiproteolytic activities that regulate extracellular matrix (ECM) turnover. However, little is known about the expression of plasminogen/plasmin system at the site of oral submucous fibrosis (OSF)., Methods: We compared the activities of tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) between fibroblasts derived from normal buccal mucosa and OSF by using an enzyme-linked immunosorbent assay. Furthermore, arecoline, a major areca nut alkaloid, was challenged with normal buccal mucosal fibroblasts (BMFs) to elucidate whether the activities of t-PA and PAI-1 could be affected by arecoline., Results: Both t-PA and PAI-1 were found to be increased in OSF than in BMFs (P < 0.01). In addition, there was a statistically significant difference in PAI-1/t-PA ratio between OSF and BMF (P < 0.01). The addition of arecoline upregulated not only PAI-1, but also t-PA in BMFs (P < 0.05). In addition, the ratio between PAI-1 and t-PA was found to be significantly increased by a linear regression assay (P < 0.01)., Conclusion: These results suggest that OSF caused by areca quid chewing may be the result of an imbalance in the plasminogen/plasmin system, the net result of which is increased deposition of ECM.