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journal article·2026-02Open access

Osteoclast‐Derived SLIT3 Mediates Osteoarthritis Pain and Degenerative Changes

Weiwei Zhu, Wenpin Qin, Jialu Gao, Yihan Guo, Xiaoxiao Han, Zhangyu Ma, Xiaokang Zhang, Jie He, Jing Liu, Bo Gao, Changjun Li, Lina Niu, Jianfei Yan, Kai Jiao

Advanced Science· Volume 13· Issue 7
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Abstract

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.
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Research context

OpenAlex topics: Axon Guidance and Neuronal Signaling · Wnt/β-catenin signaling in development and cancer · Hedgehog Signaling Pathway Studies

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Stomatology Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

Institute of Orthopaedic Surgery Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710032 China

Department of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University National Clinical Research Center for Geriatric Disorders Xiangya Hospital Key Laboratory of Organ Injury Aging and Regenerative Medicine of Hunan Province Changsha Hunan 410000 China

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Clinical Research Center for Oral Diseases Department of Oral and Maxillofacial Surgery School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China

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