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Neurogenesis is considered a key initiating factor in this pain; however, the precise mechanisms remain unclear. This study tests the hypothesis that osteoclast\u2010derived slit guidance ligand 3 (SLIT3) plays an important role in osteoarthritis pain. These findings reveal that in TMJ\u2010OA mice, increased osteoclast activation and SLIT3 expression occur in the subchondral bone of the TMJ condyle, accompanied with pain. Interestingly, results from immunofluorescent co\u2010staining and fluorescence\u2010activated cell sorting support that osteoclasts serve as the primary cellular source of SLIT3 in subchondral bone, and SLIT3 produced by TRAP\u2010positive (TRAP\n                    <jats:sup>+<\/jats:sup>\n                    ) osteoclasts significantly promotes the growth of sensory nerves. The results of in vivo models demonstrate that the specific knockdown\/knockout of\n                    <jats:italic>Slit3<\/jats:italic>\n                    in TRAP\n                    <jats:sup>+<\/jats:sup>\n                    osteoclasts significantly reduces the level of SLIT3. More importantly,\n                    <jats:italic>Slit3<\/jats:italic>\n                    knockdown\/knockout in osteoclasts results in reduced sensory nerve innervation in the osteochondral regions, decreased osteoarthritis pain, and alleviated bone and cartilage degeneration in TMJ\u2010OA. Thus, SLIT3 derived from TRAP\n                    <jats:sup>+<\/jats:sup>\n                    osteoclasts in the subchondral bone plays a crucial role in the progression of TMJ\u2010OA. This suggests that targeting SLIT3 might represent a promising therapeutic approach to alleviate the pain in TMJ\u2010OA.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517545","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:15:52Z","timestamp":1763543752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Osteoclast\u2010Derived SLIT3 Mediates Osteoarthritis Pain and Degenerative Changes"],"prefix":"10.1002","volume":"13","author":[{"given":"Weiwei","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Stomatology Tangdu Hospital &amp; State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration &amp; School of Stomatology The Fourth Military Medical University  Xi'an Shaanxi 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenpin","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Stomatology Tangdu Hospital &amp; 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