m6A demethylase Fto regulates TNF-α-induced inflammatory response in cementoblasts

Abstract

Apical periodontitis is among the most frequently occurring pathological lesions around the root apex, which can cause alveolar bone defect and tooth loss, even leading to rheumatoid arthritis, cardiovascular diseases, and diabetes. The exactly underlying molecular mechanisms are still evolving. Fat mass and obesity-associated protein (Fto) is the first identified RNA m6A demethylase/eraser that plays key regulatory roles in multiple biological processes. However, it remains unclear whether Fto is involved in the inflammatory response in cementoblasts. In the current study, we investigated the effect of tumor necrosis factor-alpha (TNF-α)-induced Fto expression in mouse cementoblast cell line (OCCM-30 cells). Following apical periodontitis induction, mice showed downregulation in the expression of Fto, associated with a significant increase in the inflammatory cell infiltration around the root apex. Moreover, OCCM-30 cells exposed to TNF-α showed similar changes, which presented an upregulation in inflammatory-related genes, whereas a decrease of Fto. Furthermore, qRT-PCR and ELISA analysis showed knockdown of Fto promoted in the expression of Il-6, Mcp1, and Mmp9 in TNF-α-treated OCCM-30 cells as compared to NC cells, whereas did not affect the mRNA stability. Interestingly, Fto knockdown activated the p65, p38, and ERK1/2 but not JNK signaling pathways after TNF-α administration in OCCM-30 cells. Taken together, these data suggest that TNF-α decreasing expression of Fto might play a critical role in the inflammatory response, and modulation of Fto might change the inflammatory response.