Abstract
Inflammation driven by the innate immune response plays a crucial role in osteoarthritis (OA) pathogenesis, yet the underlying mechanisms remain incompletely understood. Moreover, current antiinflammatory therapies primarily offer symptomatic relief without altering disease progression. Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that detects a broad range of microbial and damage-associated stimuli and has been implicated in several inflammatory conditions. In this study, we investigated the role of NOD2 in OA-associated inflammation and cartilage degradation. Elevated NOD2 expression was observed in both human and mouse osteoarthritic cartilage. Conditional KO of Nod2 in chondrocytes suppressed inflammation-induced catabolic responses in vitro and protected against cartilage degradation in mouse OA models. Mechanistically, we identified tumor necrosis factor receptor–associated factor 6 (TRAF6) as a key downstream mediator through which NOD2 promotes chondrocyte catabolism. Furthermore, we showed that pharmacological inhibition of NOD2 using 2 independent small-molecule inhibitors significantly attenuated OA progression in vivo. Collectively, these findings establish NOD2 as a critical regulator of OA-associated inflammation and cartilage degradation, and they highlight its potential as a therapeutic target for disease-modifying OA treatment.
Authors
Yuting Wang, Song Li, Yonghui Dong, Jiaming Zhang, Jian Liu, Zhenggang Wang, Shuang Liang, Nathan R. Martinez, Hongxu Pu, Peng Cheng, Anmin Chen, Qing Yang, Charles K.F. Chan, Wen Jiang, Jun Xiao, Fengjing Guo, Liming Zhao
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