NLRP3 inflammasome activation drives psychological stress-induced TMJOA through chondrocyte pyroptosis

Abstract

Psychological stress, an increasingly serious social problem, is widely recognized as a contributing factor to temporomandibular joint disorders (TMDs). However, whether it could directly cause temporomandibular joint osteoarthritis (TMJOA) is still unknown. This study aimed to investigate the role of psychological stress in the pathogenesis of TMJOA and its underlying mechanisms. A mouse model of psychological stress was constructed using a chronic unpredictable mild stress (CUMS) paradigm. Histological analyses were conducted to evaluate pathological changes in condylar cartilage and knee joint cartilage. Immunohistochemistry and quantitative real-time PCR (qRT-PCR) were used to detect nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression and its downstream pyroptosis-related factors. Furthermore, chondrocyte-specific Nlrp3 knockout mice were generated to validate the critical role of NLRP3 in psychological stress-induced TMJOA. Research revealed that, specific to the temporomandibular joint (TMJ), psychological stress induced degradation of the condylar cartilage extracellular matrix (ECM) and structural disruption in mice, ultimately leading to TMJOA, while no comparable pathology was observed in the knee joint cartilage. Mechanistically, psychological stress activated NLRP3 in condylar cartilage and triggered the classical pyroptosis pathway. Importantly, The Nlrp3 chondrocyte-specific knockout significantly alleviated psychological stress-induced cartilage destruction. Taken together, the findings of this study confirm that psychological stress is an important risk factor for TMJOA, revealing the central role of NLRP3 and highlighting its potential as a therapeutic target, which lays the theoretical foundation for novel interventions against psychological stress-induced TMJOA.

The authors' abstract, as published at the source. Cell & Bioscience, 2026 · DOI ↗