Osteoclast‐Derived SLIT3 Mediates Osteoarthritis Pain and Degenerative Changes

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.