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 TGFβ1 and SMAD4, the downstream gene of TGFβ1. In TGFβ1-induced fibrosis model of primary human oral submucous fibroblast, PTMA knockdown reversed TGFβ1-induced fibrosis process through inhibiting the cell viability and proliferation of fibroblast, reducing the protein levels of PTMA, Collagen I, α-SMA and MMP9 and increasing the protein levels of SMAD4. In contrast, PTMA overexpression enhanced TGFβ1-induced fibrosis process. Taken together, PTMA is involved in TGFβ1-induced fibrosis in the primary human submucous fibroblast by regulating the expression of ECM-related markers and the downstream genes of TGFβ1. In conclusion, PTMA presents an essential autoantigen during OSF process; targeting PTMA might be a promising strategy for OSF treatment.