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Background and Objective: Neurotrophin receptor‐interacting MAGE homologue (NRAGE) plays a crucial role in the regulation of bone metabolism. The present study investigated the regulation role of NRAGE on autophagy activation and periodontitis process during experimental periodontitis. Materials and Methods: Six‐week‐old wild‐type (WT) and NRAGE−/− mice were randomly divided into three time points in the periodontitis groups (0, 2, and 4 weeks). Histopathological changes were determined using the tooth mobility, hematoxylin and eosin (H&E) staining, and micro‐computed tomography (micro‐CT). Osteoclasts activation and number were investigated using tartrate‐resistant acid phosphatase (TRAP) staining, immunohistochemistry, and real‐time quantitative PCR (RT‐PCR). The level of autophagy‐related gene expression was measured using immunohistochemistry, immunofluorescence, and RT‐PCR. Results: H&E staining and Micro‐CT showed that the destruction of the alveolar bone was considerably more severe in the NRAGE−/− group than the WT group after ligation. Tooth mobility in the NRAGE−/− group was obviously higher than that in the WT group. The activation and number of osteoclasts and the level of autophagy‐related gene expression in NRAGE−/− group were significantly higher than that in WT group. Conclusions: The present study showed that knockout of NRAGE induced autophagy‐related gene expression and accelerated the process of periodontitis disease via increasing the activity and differentiation of osteoclast. [ABSTRACT FROM AUTHOR]