Identification of Synovial Lymphatics in the TMJ and their Roles in Arthritis and Pain.

Temporomandibular joint (TMJ) arthritis is a craniofacial disorder characterized by joint dysfunction and orofacial pain. Lymphatic regulation and function in the TMJ remain unknown. Using genetic reporter mice, human tissues, tissue clearing, 3D volume imaging, and functional studies, we identified a synovial lymphatic system in the TMJ. In a mouse model of TMJ arthritis, inflammation induces extensive lymphatic remodeling and leads to synovial lymphatic dysfunctions, including decreases in synovial efflux and lymph node fluid drainage. Functional genetics and single-cell RNA sequencing (scRNA-seq) revealed that lymphatic deficiency induces a population of fibrosis-associated macrophages and enhances inflammation, exacerbating cartilage defects, bone loss, synovitis, and pain behaviors in TMJ arthritis mice. Conversely, lymphatic function promotion via a hydrogel-mediated VEGF-C delivery reduced TMJ pain, inflammation, and arthritis-like pathogenesis. For the first time, we identified synovial lymphatics in the TMJ and found that lymphatic dysfunction drives TMJ arthritis and pain, suggesting its potential as a therapeutic target.