The Function of Efhd1 ⁺ Telocytes in the Synovial Lymphatic System and Inflammatory-Erosive Arthritis

Resting collecting lymphatic vessels (cLVs) sense edema in distal joints and initiate contractions via unknown mechanisms. Rheumatoid arthritis (RA) patients have lymphatic drainage deficiencies from affected joints, and defects in the synovial lymphatic system exacerbate inflammatory-erosive arthritis in animal models. To understand this, we generated Efhd1 -CreER ^T2 and Myoc -CreER ^T2 mice for cell-specific genetic gain and loss of function studies. These mice were crossed with tdTomato reporter (Ai9) mice, and studies showed selective tamoxifen-induced transgene expression in CD31 ^- /CD34 ⁺ telocyte-like cells in knee and ankle synovium, and in networks physically associated with mast cells proximal to popliteal lymphatic vessels (PLVs). Consistent with the known loss of CD31 ^- /CD34 ⁺ telocyte in RA synovium, these cells were also decreased in TNF-tg knees and partially recovered by anti-TNF treatment. Ultrastructural and gene expression studies confirmed a distinct telocyte phenotype versus closely related fibroblasts. In vivo depletion studies in tamoxifen-treated Efhd1 -CreER ^T2 and Myoc -CreER ^T2 mice crossed to diphtheria toxin alpha-floxed (DTA ^flox ) mice demonstrated telocyte requirements for physiologic lymphatic drainage and resolution of joint inflammation and focal erosions from zymosan-induced arthritis in the knee. In vitro studies demonstrated increased sensitivity to osmotic shock and decreased motility versus fibroblasts, and telocyte potential to differentiate into myofibroblasts on stiff matrix. Collectively, these findings support a model of joint homeostasis in which osmotic pressure-sensing telocyte networks extend from the synovium into mast cells proximal to joint-draining cLVs, and telocyte loss is associated with defects in the synovial lymphatic system and increased susceptibility to joint inflammation and structural damage from arthritis.