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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\n                    <jats:italic>Nod2<\/jats:italic>\n                    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\u2013associated 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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.196750","type":"journal-article","created":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:01:06Z","timestamp":1787508066000},"source":"Crossref","is-referenced-by-count":0,"title":["Innate immune sensor NOD2 promotes cartilage degradation and osteoarthritis progression by stabilizing TRAF6 in chondrocytes"],"prefix":"10.1172","volume":"11","author":[{"given":"Yuting","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China."},{"name":"Institute for Stem Cell Biology and Regenerative Medicine and"},{"name":"Department of Surgery, Division of Plastic and Reconstructive 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