Synovial lymphatic system structure and function in rheumatoid arthritis: lymphatic phases, telocytes, and therapeutic modulation through Eexercise.

Lymphatic changes are associated with rheumatoid arthritis (RA), commencing with lymphangiogenesis in the "expanding phase", which transitions to the "collapsed phase" with dysfunction and advanced disease. Here, we review our understanding of the synovial lymphatic system (SLS) during joint homeostasis and arthritis, and the potential of exercise therapy. How collecting lymphatic vessels (cLV) responsible for joint drainage sense effusion is unknown. Recently, murine models identified peri-cLV telocytes (interstitial mesenchymal cells involved in tissue maintenance and the regulation of muscle contraction). These telocytes were found buried within the rich extracellular matrix (ECM) of the cLV, and in networks extending from the synovium to the joint-draining cLV. In vivo telocyte depletion studies demonstrated decreased lymphatic drainage and exacerbated synovitis and bone erosions during zymosan-induced arthritis. Gene expression studies demonstrated that Efhd1, Dpp4, and Pi16 are specific markers of human and murine synovial telocytes, which are absent in RA synovium and mice with inflammatory arthritis. Preliminary studies demonstrate that ad libitum exercise increases the number of synovial telocytes in mice. Telocytes maintain the ECM of the SLS and may transmit signals to joint-draining cLV. Telocyte loss is associated with arthritic progression, which may be abated with exercise.