Identification of synovial lymphatic system in the temporomandibular joint 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 TMJ remain unknown. Using genetic reporter mice, human tissues, tissue clearing, 3D volume imaging, and functional studies, we identified a synovial lymphatic system in TMJ. In a mouse model of TMJ arthritis, inflammation induces extensive lymphatic remodeling and leads to synovial lymphatic dysfunctions. Functional genetics and single-cell RNA sequencing (scRNA-seq) revealed that lymphatic deficiency induces a population of fibroblast-macrophage hybrid cells 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 prevents TMJ pain, inflammation, and arthritis-like pathogenesis. Thus, we identified synovial lymphatics in TMJ and found that lymphatic dysfunction drives TMJ arthritis and pain, suggesting its potential as a therapeutic target. Here, the authors show that the temporomandibular joint contains a previously unrecognized synovial lymphatic network. Disrupted lymphatics in inflammatory arthritis amplify synovitis, cartilage degeneration, bone loss, and pain behaviors, whereas enhancing lymphatic activity restores drainage, reduces inflammation, and alleviates pain.