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Despite advancements in understanding TMJOA pathogenesis, the molecular mechanisms underlying its progression remain unclear. In this study, elevated Slit guidance ligand 2 (SLIT2) expression was observed in TMJ tissues of unilateral anterior crossbite\u2013induced TMJOA mice and synovial fluid from patients with TMJOA, correlating with disease severity. Furthermore, SLIT2 overexpression in transgenic mice intensified TMJOA progression, whereas heterozygous deletion of roundabout guidance receptor 1\/2 (ROBO1\/2) alleviated cartilage and bone damage. Mechanistically, SLIT2 promoted ROBO1-LRP6 complex formation, facilitating LRP6 phosphorylation and \u03b2-catenin nuclear translocation. This cascade upregulated matrix-degrading enzymes while downregulating cartilage structural proteins, exacerbating cartilage destruction and subchondral bone loss. These findings suggest that the SLIT2\/ROBO1\/LRP6 axis may represent a potential therapeutic target for TMJOA and provide mechanistic insights into disease progression.<\/jats:p>","DOI":"10.1172\/jci.insight.193632","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T18:00:46Z","timestamp":1775584846000},"source":"Crossref","is-referenced-by-count":0,"title":["Activation of SLIT2\/ROBO1\/LRP6 axis aggravates cartilage degradation via \u03b2-catenin signaling in TMJOA"],"prefix":"10.1172","volume":"11","author":[{"given":"Guan","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Orthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, Guangdong, 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