Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.
Humans ; Oral Submucous Fibrosis/immunology* ; Extracellular Matrix/metabolism* ; Myofibroblasts

Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis (OSF). However, the precise characteristics and underlying mechanisms remain unclear, impeding the advancement of potential therapeutic approaches. Here, we observed that collagen I, the main component of the extracellular matrix, first accumulated in the lamina propria and subsequently in the submucosa of OSF specimens as the disease progressed. Using RNA-seq and Immunofluorescence in OSF specimens, we screened the cartilage oligomeric matrix protein (COMP) responsible for the abnormal collagen accumulation. Genetic COMP deficiency reduced arecoline-stimulated collagen I deposition significantly in vivo. In comparison, both COMP and collagen I were upregulated under arecoline stimulation in wild-type mice. Human oral buccal mucosal fibroblasts (hBMFs) also exhibited increased secretion of COMP and collagen I after stimulation in vitro. COMP knockdown in hBMFs downregulates arecoline-stimulated collagen I secretion. We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation, of which COMP-positive fibroblasts secrete more collagen I. Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices (FACIT) in the collagen network, we further screened and identified collagen XIV, a FACIT member, co-localizing with both COMP and collagen I. Collagen XIV expression increased under arecoline stimulation in wild-type mice, whereas it was hardly expressed in the Comp^-/- mice, even with under stimulation. In summary, we found that COMP may mediates abnormal collagen I deposition by functions with collagen XIV during the progression of OSF, suggesting its potential to be targeted in treating OSF.
Oral Submucous Fibrosis/pathology* ; Cartilage Oligomeric Matrix Protein/genetics* ; Animals ; Mice ; Humans ; Fibroblasts/metabolism* ; Collagen Type I/metabolism* ; Arecoline/pharmacology* ; Mouth Mucosa/metabolism* ; Cells, Cultured ; Fluorescent Antibody Technique

As the field of oral pathology has evolved, the nomenclature and classification of oral mucosal diseases with a remarkable risk of malignant transformation have undergone several modifications. In 2005, the World Health Organization (WHO) introduced the concept of oral potentially malignant disorders (OPMDs) as an alternative to the terms for oral precancerous lesions and precancerous conditions. In the consensus report by the WHO Collaborating Center for Oral Cancer of 2021, OPMD is defined as "any oral mucosal abnormality that is associated with a statistically increased risk of developing oral cancer."This definition encompasses a range of conditions, in-cluding oral leukoplakia, oral submucous fibrosis, proliferative verrucous leukoplakia, oral lichen planus, and other lesions. In light of the complex etiology, unclear pathogenesis, and carcinogenesis of OPMDs, early and precise diagnosis and treatment can contribute to the secondary prevention of oral cancer. For this reason, this review, which aims to provide a basis for the precise clinical diagnosis of OPMDs, was performed. Its aim was achieved by reviewing the historical evolution and research progress of the nomenclature, classification, and histopathological diagnostic criteria of OPMDs.
Humans ; Mouth Neoplasms/diagnosis* ; Precancerous Conditions/diagnosis* ; Leukoplakia, Oral/diagnosis* ; Lichen Planus, Oral/pathology* ; Oral Submucous Fibrosis/pathology* ; Mouth Mucosa/pathology* ; World Health Organization

OBJECTIVES: There is currently a lack of economic and suitable animal models that can accurately recapitulate the oral submucous fibrosis (OSF) disease state for indepth study. This is one of the primary reasons for the limited therapeutic methods available for OSF. Based on the underlying logic of pan-cancer analysis, this study systematically compares OSF and the other four types of organ fibrosis from the aspects of molecules, signaling pathways, biological processes, etc. A comprehensive analysis of the similarities and differences between OSF and other organ fibrosis is helpful for researchers to discover some general rules of fibrosis disease and may provide new ideas for studying OSF. METHODS: Microarray data of the GSE64216, GSE76882, GSE171294, GSE92592, and GSE90051 datasets were downloaded from GEO. Differentially expressed mRNAs (DEmRNAs) of each type of fibrosis were identified by Limma package. Weighted gene co-expression network analysis (WGCNA) was used to identify each type of fibrosis-related module. The similarities and differences of each fibrosis-related-module genes were analyzed by function and pathway enrichment analysis. RESULTS: A total of 6 057, 10 910, 27 990, 10 480, and 4 801 DEmRNAs were identified in OSF, kidney intestinal fibrosis (KIF), liver fibrosis (LF), idiopathic pulmonary fibrosis (IPF), and skin fibrosis (SF), respectively. By using WGCNA, each type of fibrosis-related module was identified. The co-expression networks for each type of fibrosis were constructed respectively. Except that KIF and LF have 5 common hub genes, other fibrotic diseases have no common hub genes with each other. The common pathways of OSF, KIF, LF, IPF, and SF mainly focus on immune-related pathways. CONCLUSIONS OSF and the other 4 types of fibrotic diseases are tissue- and organ-specific at the molecular level, but they share many common signaling pathways and biological processes, mainly in inflammation and immunity.
Animals ; Oral Submucous Fibrosis/genetics* ; Gene Expression Profiling ; Inflammation ; Signal Transduction ; Fibrosis

OBJECTIVES: This study was performed to review the efficacy of curcumin in the treatment of oral submucous fibrosis systematically. METHODS: We searched seven databases, including Web of Science, PubMed, EBSCO, The Cochrane Library, CNKI, WanFang Data, and VIP, to obtain randomized controlled trials related to the treatment of oral submucous fibrosis by curcumin. Each database was searched from inception to 30 June 2019. RevMan 5.3 software was used for the meta-analysis. RESULTS: Six randomized controlled trials involving 350 patients were included in this study. Meta-analysis showed that curcumin can increase the maximal mouth opening and improve burning sensation compared with placebo treatment. Curcumin was not as effective as the controls in achieving maximal mouth opening after 1 month of treatment. However, no statistically significant difference was observed between the treatments from 2 months to 6 months. Curcumin significantly improved burning sensation compared with the controls after 3 months of treatment. No statistically significant diffe-rence in burning sensation was observed between the curcumin and control groups after 1, 2, and 6 months of treatment. CONCLUSIONS The current evidence shows that curcumin is an effective treatment for improving maximal mouth opening and burning sensation in patients with oral submucous fibrosis. Given the limited number and low quality of the included studies, however, more high-quality studies are needed to verify these findings.
Curcumin ; Databases, Factual ; Humans ; Oral Submucous Fibrosis/drug therapy* ; Randomized Controlled Trials as Topic ; Treatment Outcome

The integrity of the basal stem cell layer is critical for epithelial homoeostasis. In this paper, we review the expression of oral mucosal stem cell markers (OM-SCMs) in oral submucous fibrosis (OSF), oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) to understand the role of basal cells in potentiating cancer stem cell behaviour in OSF. While the loss of basal cell clonogenicity triggers epithelial atrophy in OSF, the transition of the epithelium from atrophic to hyperplastic and eventually neoplastic involves the reactivation of basal stemness. The vacillating expression patterns of OM-SCMs confirm the role of keratins 5, 14, 19, CD44, β1-integrin, p63, sex-determining region Y box (SOX2), octamer-binding transcription factor 4 (Oct-4), c-MYC, B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi-1) and aldehyde dehydrogenase 1 (ALDH1) in OSF, OPMDs and OSCC. The downregulation of OM-SCMs in the atrophic epithelium of OSF and their upregulation during malignant transformation are illustrated with relevant literature in this review.
Animals ; Carcinoma, Squamous Cell ; pathology ; Cell Transformation, Neoplastic ; pathology ; Mice ; Mouth Mucosa ; Mouth Neoplasms ; pathology ; Oral Submucous Fibrosis ; pathology ; Stem Cells

The relationship between areca nut as a primary carcinogen and oral cancer has been widely concerned. Areca can change the levels of reactive oxygen species (ROS) and autophagy in cells, and the levels of ROS and autophagy are closely related to the occurrence and development of tumors. This paper reviewed the relationships among areca nut, intracellular ROS, and autophagy.
Areca ; Autophagy ; Humans ; Mouth Neoplasms ; Nuts ; Oral Submucous Fibrosis ; Reactive Oxygen Species

OBJECTIVE: The aim of this study was to induce oral submucous fibrosis (OSF) in Sprague-Dawley(SD) rat models by arecoline and mechanical stimulation. METHODS: Two factors factorial design was used to divide 48 rats into 8 groups (n=6). Different concentrations of arecoline (0, 0.5, 2, and 8 mg·mL⁻¹) and mechanical stimulation (with or without brush) were treated. After 16 weeks of treatment, the mouth opening was measured, the pathological changes of the buccal mucosa were observed, and the expressions of type Ⅲ collagen, transforming growth factor β1 (TGF-β1), and interferon-γ (IFN-γ) were detected. RESULTS: In rats with moderate and high concentrations of arecoline, typical OSF pathological features were observed in the buccal mucosa, the mouth openings were significantly reduced, and the expression levels of type Ⅲ colla-gen and TGF-β1 were significantly increased (P<0.05). Although mechanical stimulation can increase the three indexes of mucosa (P<0.05), no pathological change and difference in the mouth opening was observed (P>0.05). CONCLUSIONS Moderate and high concentrations of arecoline can induce OSF in SD rats, but mechanical stimulation cannot induce OSF.
Animals ; Arecoline ; pharmacology ; Fibroblasts ; Mouth Mucosa ; Oral Submucous Fibrosis ; Rats ; Rats, Sprague-Dawley

To evaluate therapeutic effect of combined injection of salvizanolic acid B with triamcinolone acetonide on the treatment of the soft palate with oral submucous fibrosis.
 Methods: Salvizanolic acid B combined with triamcinolone acetonide was consecutively applied once a week for 30 weeks for 33 patients with middle and later periods of oral submucous fibrosis. The response rate of color change in the soft palate and the increase of capillary vessels (determined by degree I-IV visual analog scale) were evaluated at the 12th, 24th, and 36th months after 30 weeks treatment.
 Results: Thirty-three patients were fulfilled the study without obvious adverse reactions and they were followed up for 24 months, while 31 patients were followed up for 36 months. The color change in the soft palatal mucus and the increase of capillary vessels at the 36th month follow-up after treatment were significantly better than those at the 12th month (P=0.004).
 Conclusion: Combined injection of salvizanolic acid B with triamcinolone acetonide in the treatment of the soft palate with oral submucous fibrosis is effective.
Glucocorticoids ; Humans ; Oral Submucous Fibrosis ; drug therapy ; Palate, Soft ; Treatment Outcome ; Triamcinolone Acetonide ; therapeutic use

To analyze the incidence and distribution of oral mucosal diseases in Hunan Province and provide reference for prevention and treatment.
 Methods: The clinical data for all patients, who were treated in Xiangya Hospital of Central South University from April 2013 to March 2017, were collected. After screening, weighing and classifying, sex and age distribution for the disease was analyzed.
 Results: The female with the age between 40 to 49 were in the majority among 21 972 patients. The ratio between men to women was 1:1.05. According to the classification of diseases, the most common diseases were as follows: recurrent aphthous ulcer (27.17%), burning mouth syndrome (15.72%), oral submucous fibrosis (14.75%), oral lichen planus (10.38%), oral leukoplakia (4.21%), traumatic ulceration (4.14%), chronic cheilitis (3.47%), oral fungal infection (3.26%), and atrophic glossitis (2.74%). Recurrent oral ulcer (28.65%), burning mouth syndrome (23.70%) and oral lichen planus (13.31%) were the most common 3 kinds of oral mucosal diseases during females in Hunan. Oral submucous fibrosis was the most common oral mucosal disease among males in Hunan (28.56%).
 Conclusion: Recurrent oral ulcer, burning mouth syndrome and oral lichen planus are very popular in women in Hunan Province, and oral submucous fibrosis is the most common disease in male in this region. It shows a high trend of incidence in the surrounding provinces.
Adult ; Age Distribution ; Burning Mouth Syndrome ; epidemiology ; China ; epidemiology ; Female ; Fibrosis ; Humans ; Incidence ; Leukoplakia, Oral ; epidemiology ; Lichen Planus, Oral ; epidemiology ; Male ; Middle Aged ; Mouth Diseases ; epidemiology ; therapy ; Mouth Mucosa ; pathology ; Oral Submucous Fibrosis ; Oral Ulcer ; epidemiology ; Sex Distribution ; Stomatitis, Aphthous ; epidemiology