Osteoclast‐Derived SLIT3 Mediates Osteoarthritis Pain and Degenerative Changes

Abstract Temporomandibular joint osteoarthritis (TMJ‐OA) is a prevalent degenerative joint disease that significantly impairs quality of life. Neurogenesis is considered a key initiating factor in this pain; however, the precise mechanisms remain unclear. This study tests the hypothesis that osteoclast‐derived slit guidance ligand 3 (SLIT3) plays an important role in osteoarthritis pain. These findings reveal that in TMJ‐OA mice, increased osteoclast activation and SLIT3 expression occur in the subchondral bone of the TMJ condyle, accompanied with pain. Interestingly, results from immunofluorescent co‐staining and fluorescence‐activated cell sorting support that osteoclasts serve as the primary cellular source of SLIT3 in subchondral bone, and SLIT3 produced by TRAP‐positive (TRAP + ) osteoclasts significantly promotes the growth of sensory nerves. The results of in vivo models demonstrate that the specific knockdown/knockout of Slit3 in TRAP + osteoclasts significantly reduces the level of SLIT3. More importantly, Slit3 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‐OA. Thus, SLIT3 derived from TRAP + osteoclasts in the subchondral bone plays a crucial role in the progression of TMJ‐OA. This suggests that targeting SLIT3 might represent a promising therapeutic approach to alleviate the pain in TMJ‐OA.