Mechanical force activates KCNN4 to regulate NLRP3 inflammasome in periodontal ligament cells during orthodontic tooth movement.

Authors

Fu Zheng, Feifei Wang, Peng Chen, Peng Wang, Chen Yang, Chonghao Ji, Zuping Wu, Xinyi Fang, Xinlei Yu, Lehan Xu, Jing Zhou, Rui Zhang, Gaofeng Li, Peng Deng, Qianming Chen, Xiaoyan Chen

Published in

Journal of advanced research. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Orthodontic tooth movement (OTM) relies on mechanical force that triggers inflammatory responses in periodontal tissue, orchestrating alveolar bone remodeling. Potassium (K⁺) efflux plays a key role in inflammation and tissue remodeling. The calcium-activated potassium channel KCNN4 regulates immune responses, but its role in inflammatory signaling in periodontal ligament cells (PDLCs) under mechanical stress remains unclear.
This study aimed to investigate how mechanical force activates KCNN4 and regulates downstream inflammatory signaling in PDLCs.
Human PDLCs (hPDLCs) were subjected to compressive force in vitro. KCNN4, FOXO1, and USP46 were interfered with using pharmacological inhibition (senicapoc) or siRNA-mediated knockdown. Potassium and calcium fluxes, NLRP3 inflammasome activation, and downstream cytokine expression were assessed via fluorescence imaging, western blotting, qPCR, and immunoprecipitation. Chromatin immunoprecipitation and RNA-seq analyses were performed to identify transcriptional regulators of USP46. Conditioned medium from hPDLCs was applied to THP-1-derived macrophages to evaluate macrophage inflammatory polarization. In vivo, a rat OTM model was used to examine alveolar bone remodeling and local inflammation under KCNN4 inhibition. TRAP staining, immunohistochemistry, and immunofluorescence to evaluate osteoclast activity and NLRP3-mediated inflammatory signaling in the periodontal ligament.
Mechanical force induced KCNN4-mediated K⁺ efflux in hPDLCs, promoting FOXO1 dephosphorylation and nuclear translocation. Activated FOXO1 transcriptionally upregulated the deubiquitinase USP46, which in turn deubiquitinated NLRP3, leading to inflammasome activation. Inhibition of KCNN4, FOXO1, or USP46 attenuated NLRP3 activation and downstream IL-1β maturation. Conditioned medium experiments demonstrated that this signaling cascade promoted macrophage inflammatory activation, while senicapoc reversed these effects. In vivo, KCNN4 inhibition suppressed local NLRP3-mediated inflammation, reduced osteoclast differentiation on the pressure side, and attenuated OTM.
Our findings reveal a mechanotransduction axis in PDLCs whereby mechanical force activates KCNN4, driving FOXO1-dependent USP46 transcription and NLRP3 inflammasome activation. This signaling cascade translates transient mechanical stimuli into an inflammatory cascade, triggering macrophage-mediated alveolar bone remodeling during OTM. Importantly, KCNN4 is required for proper inflammatory responses and OTM, highlighting its potential role in orthodontic therapy.

PMID:
42628920
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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