Sidt2 Knockdown Aggravates Apical Periodontitis Via Autocrine Tumour Necrosis Factor-Alpha.

OBJECTIVE: Apical periodontitis (AP) is characterised by inflammatory infiltration and periapical bone loss, accompanied by high expression of tumour necrosis factor-alpha (TNF-α). SID1 transmembrane family member 2 (Sidt2) is a lysosomal membrane protein associated with inflammation. However, the effect of Sidt2 on AP remains unknown.

METHODS: We established an AP mouse model, and then the adenovirus-associated virus was used to inhibit Sidt2 expression in the AP model. Periapical lesions were detected using micro-computed tomography. Haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, and immunohistochemistry staining were conducted to explore the roles of Sidt2 in inflammation and osteoclast differentiation in AP; F-actin staining, quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay and RNA sequencing analysis were used to detect osteoclast differentiation and TNF-α signalling pathway in RAW 264.7 cells.

RESULTS: Sidt2 was suppressed, and TNF-α was increased in AP. Sidt2 knockdown aggravated inflammation and bone loss in AP. Besides, Sidt2 inhibition upregulated osteoclast differentiation both in AP and in RAW 264.7 cells. Mechanistically, RNA sequencing analysis revealed Sidt2 may regulate osteoclast differentiation via the TNF-α signalling pathway. Profoundly, knockdown Sidt2 enhanced TNF-α production and secretion, while neutralising TNF-α partially relieved Sidt2-knockdown-increased osteoclast differentiation in RAW 264.7 cells.

CONCLUSION: Our data demonstrated that Sidt2 negatively regulates autocrine TNF-α signalling to participate in osteoclast differentiation in AP, supporting the notion that Sidt2 may serve as a therapeutic target for bone resorption.