Regular articleIMMUNOLOCALIZATION OF CYTOKINES AND GROWTH FACTORS IN ORAL SUBMUCOUS FIBROSIS
Abstract
Oral submucous fibrosis (OSF) is a chronic fibrotic disease of the oral cavity and oropharynx characterized by fibroelastic change in the mucosa which leads to progressive inability to open the mouth. The inflammatory cells in the lesional tissue consist mainly of T lymphocytes, with a high CD4:CD8 ratio, and major histocompatibility complex (MHC) class II expressing antigen-presenting cells. Cytokines and growth factors produced by inflammatory cells within the lesion may promote fibrosis by inducing proliferation of fibroblasts, upregulating collagen synthesis and downregulating collagenase production. The authors used a three-stage immunoperoxidase technique to investigate the expression of interleukin α (IL-1α) and β, IL-6 interferon (IFN)-α, β and γ, transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in frozen sections of OSF and compared it with that in normal buccal mucosa. The expression of cytokines and growth factors in normal tissues was consistent with their well known distribution and cell of origin, but the intensity and distribution in OSF were all, with the exception of IFN-α and γ, upregulated with strong expression in both the epithelium and underlying connective tissue. IFN-α showed a similar pattern of staining in both normal mucosa and OSF. IFN-γ showed little or no expression in most lesional tissues, suggesting an innate deficiency or downregulation of this cytokine. The general increase in pro-inflammatory cytokines and growth factors, and reduced production of IFN-γ, may play an important role in the pathogenesis of OSF.
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Inhibition of lncRNA HOTTIP ameliorated myofibroblast activities and inflammatory cytokines in oral submucous fibrosis
2021, Journal of the Formosan Medical AssociationLong non-coding RNA HOXA transcript at the distal tip (HOTTIP) has been reported to contribute to multiple carcinomas, but whether it involves in the progression of precancerous conditions remains to be determined. Oral submucous fibrosis (OSF) has been known as an oral potentially malignant disorder and attributed to the persistent activation of the myofibroblast.
The relative expression of HOTTIP in OSF tissues has been employed by RNA-sequencing and RT-PCR analysis. HOTTIP associated myofibroblasts activities and markers in fibrotic buccal mucosal fibroblast (fBMFs) through loss of function approaches have been evaluated.
In the present study, we found that the expression of HOTTIP was overexpressed in the OSF tissues and positively correlated with several fibrosis markers. To investigate its significance of myofibroblast activation, we first verified the expression level of HOTTIP in the patient-derived fibrotic buccal mucosal fibroblast (fBMFs) was upregulated and conducted the shRNA-mediated knockdown experiment to inhibit its expression followed by numerous examinations. We demonstrated that suppression of HOTTIP downregulated the expression of myofibroblast marker, α-SMA, and type I collagen along with the diminished myofibroblast activities (collagen gel contraction and migration capacities). Furthermore, we showed that silencing HOTTIP lessened the production of various pro-inflammatory cytokines (IL-6 and TNF-α).
Collectively, our results suggest that HOTTIP plays a crucial role in the persistent activation of myofibroblasts as well as the chronic inflammation and collagen deposition.
Role of matrix metalloproteinase-9 polymorphisms in basement membrane degradation and pathogenesis of oral submucous fibrosis
2018, Meta GeneOral submucous fibrosis (OSMF) is regarded as a collagen and collagenase metabolic disorder. Aberrant expression of matrix metalloproteinases (especially MMP-9) plays important role in remodeling of extracellular matrix (ECM) during development of OSMF. Single nucleotide polymorphisms (SNPs) in MMP-9 promoter and coding region have been demonstrated to be associated with several diseases. In this case-control study, 196 controls and 189 OSMF patients were genotyped at four MMP-9 polymorphic sites on −1562C>T, R279Q, P574R and R688Q loci by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) method to determine the susceptibility to OSMF. The functional effect of SNPs to the development of OSMF was analyzed by studying the expression of MMP-9, collagen type-I and IV in oral biopsy tissues. R279Q SNP was found to be associated with OSMF [OR 1.5, CI (1.04–2.43), p = 0.03]. The 574R and 668Q alleles were significantly associated with early age group at 2.08 (p = 0.007) and 2.12 (p = 0.011) fold risk to OSMF respectively. MDR analysis showed that -1562C>T and R688Q SNPs were in strong synergy (IG = 0.95%, p = 0.0032) with increased risk of OSMF. Genotypic and functional study revealed definitive role of MMP-9 coding SNPs R279Q, P574R and R668Q in the pathogenesis of OSMF with strong predictive and prognostic value to determine OSMF at early stages in the areca chewers. Pathologically, over-expression of MMP-9 leads to decrease in collagen type-IV and epithelial thinning which contribute to basement membrane degradation along with continuous accumulation of collagen type-I enhanced by MMP-9 −1562C>T, R279Q, P574R and R688Q SNPs, resulting into early onset of OSMF.
Expression of β1integrin in normal epithelium, oral submucous fibrosis and oral squamous cell carcinoma
2018, Pathology Research and PracticeThe possible reason suggested for epithelial atrophy in oral submucous fibrosis (OSMF) is ischemia. Dysregulation in the epithelial proliferation and maturation is also thought to be a cause. The β1 integrin identifies the oral epithelial stem cells. The changes induced by the arecanut on these cells may result in epithelial alterations. The aim of this study is to evaluate the stem cells distribution and percentage by assessing the β1 integrin expression.
The study included normal oral mucosa (15 cases) and disease group (97 cases). The disease group was further subdivided into early (29 cases), moderate (34 cases), advanced OSMF (18 cases) and oral squamous cell carcinoma(OSCC) associated with OSMF (16 cases). The tissues were stained for β1 integrin antibodies. The positive cells and staining intensities were analysed to determine the staining index, and statistically evaluated using KW test statistics.
β1 integrin was observed in retepegs region and the percentage of positive cells was 14%– 30% in the control. In OSMF, the β1 integrin positivity was observed in basal and suprabasal layers, and the percentage was ranged from 2%–71%. β1 integrin expression in OSCC was observed both in central and peripheral cells and ranged from 17%–85%. On comparison, the difference in staining index among normal, OSMF and carcinomas was significant at p < 0.01. The stem cells percentage was increased both in OSMF and carcinomas. The non-dysplastic epithelium of OSMF with severe atrophy showed lowest percentage. It is inferred that absence of stem cells and proliferation may attribute for the atrophy.
Expression of transforming growth factor beta in oral submucous fibrosis
2020, Journal of Oral Biology and Craniofacial ResearchOral submucous fibrosis (OSMF) is a premalignant condition mainly caused by areca nut chewing and is characterized by progressive fibrosis of submucosal tissues and epithelial atrophy. Activation of transforming growth factor beta (TGF-β) signaling is considered main causative event for increased collagen production and fibrosis. In this study, molecular pathogenesis of OSMF was investigated based on the expression of the TGF-β genes in OSMF tissues compared to normal controls.
A total of 33 OSMF and 10 normal tissues were collected from patients and their clinic-epidemiological data was recorded. The expression of TGF-β isoform genes- TGF β1, TGF β2, TGF β3 and its receptor TGF βR1, TGF βR2 was studied by real time polymerase chain reaction (PCR). Comparison of the expression of these genes among normal controls and OSMF patients was done. The PCR results were confirmed by histopathological and immunohistochemical staining.
The histological changes included atrophic epithelium, loss of rete ridges, presence of inflammatory cells and dense collagen bundles in connective tissue. PCR showed statistically significant upregulation of TGF-β isoforms in OSMF as compared to normal tissues. Of the three isoforms, maximum fold change was observed in TGF-β1. Similarly, both TGF-βR1 and TGF-βR2 were found to be elevated in OSMF tissues compared to normal. The semi-quantitative analysis by immunohistochemical staining revealed statistically significant difference between normal and OSMF tissues.
TGF-β signaling plays a major role in the molecular pathogenesis of OSMF as shown by increased mRNA expression of all the three TGF-β isotypes and their receptors.
Langerhans cell expression in oral submucous fibrosis: An immunohistochemical analysis
2023, Journal of Oral and Maxillofacial PathologyExpression of transforming growth factor-β in oral submucous fibrosis: A systematic review
2023, Journal of Oral and Maxillofacial Pathology
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Correspondence to: Sajeda Meghji, Department of Oral and Maxillofacial Surgery, Eastman Dental Institute. 256 Gray's Inn Road, London WCIX 8LD, UK