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PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix.

ABSTRACT: Oral submucous fibrosis (OSF) is a chronic, insidious disease. The presence of autoantibodies in sera of OSF patients is the most characteristic and direct evidence of OSF being an autoimmune disease. To identify the specific autoantigens which could contribute to antibody production, the Human Proteome Microarrays composed of 19000 full-length unique proteins were employed. 45 proteins correlated with OSF were identified. To validate these results, we used ELISA to validate 28 OSF-associated autoantigens in extended samples. 8 autoantigens were positive in OSF serum with high frequency compared to the healthy controls. Moreover, the mRNA expression of 8 candidates was up-regulated in OSF oral submucous tissues; among them, the protein level of PTMA, the one with the highest positive frequency, was also increased. Through searching the Bioinformatics Public Database and performing the Spearman's rank correlation analysis, we observed that PTMA was positively correlated with fibrosis-related TGF?1 and SMAD4, the downstream gene of TGF?1. In TGF?1-induced fibrosis model of primary human oral submucous fibroblast, PTMA knockdown reversed TGF?1-induced fibrosis process through inhibiting the cell viability and proliferation of fibroblast, reducing the protein levels of PTMA, Collagen I, ?-SMA and MMP9 and increasing the protein levels of SMAD4. In contrast, PTMA overexpression enhanced TGF?1-induced fibrosis process. Taken together, PTMA is involved in TGF?1-induced fibrosis in the primary human submucous fibroblast by regulating the expression of ECM-related markers and the downstream genes of TGF?1. In conclusion, PTMA presents an essential autoantigen during OSF process; targeting PTMA might be a promising strategy for OSF treatment.

SUBMITTER: Wang J

PROVIDER: S-EPMC5650380 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix.

Wang Jie J You Jialing J Wang Lekai L Wang Huimin H Tian Tian T Wang Wenjin W Jia Lina L Jiang Canhua C

Oncotarget 20170824 43

Oral submucous fibrosis (OSF) is a chronic, insidious disease. The presence of autoantibodies in sera of OSF patients is the most characteristic and direct evidence of OSF being an autoimmune disease. To identify the specific autoantigens which could contribute to antibody production, the Human Proteome Microarrays composed of 19000 full-length unique proteins were employed. 45 proteins correlated with OSF were identified. To validate these results, we used ELISA to validate 28 OSF-associated au ...[more]

PMID: 29088825

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Project description:Background: Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. Methods: A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. Results: A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19+MIF+ epithelial cells and via epithelial-stromal crosstalk. Conclusions: Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.

Dataset Information

PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix.

Publications

PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix.

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