Targeting synovial lymphatic function as a novel therapeutic intervention for age-related osteoarthritis in mice.
Academic Article
Overview
abstract
OBJECTIVE: The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 are crucial for lymphangiogensis. However, their involvement in age-related osteoarthrits is unknown. We aim to determine whether the SLS and the VEGF-C/VEGFR3 pathway contribute to age-related osteoarthritis using a murine model of naturally occurring disease. METHODS: SLS function was assessed in young (3-month) and aged (19~24-month) C57BL/6J male mice via a newly established in vivo IVIS-Dextran imaging approach, which was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice in addition to histology. RNA sequencing was performed to explore molecular mechanisms. RESULTS: Aged mice have impaired SLS function, including decreases in: joint clearance (T1/2 2.8hr vs. 0.5hr in young, p<0.0001), synovial influx (1.7±0.8% vs. 4.1±1.9% in young, p=0.0004), and lymph node draining capacity (1.4±0.8 vs. 3.7±1.2 signal intensity in young, p<0.0001). RNA sequencing of the synovial tissue showed Vegf-c and VEGFR3 signaling genes were decreased in aged synovium. VEGF-C treatment improved joint clearance (63±9% vs. 52±15% in vehicle, p=0.012), increased articular cartilage cross-sectional area (0.38±0.07 vs. 0.26±0.07 mm2 in vehicle, p<0.0001), and decreased MMP13+ staining area (7±2 % vs. 4±1 % in vehicle, p=0.0004) in aged mice. CONCLUSION: SLS function is reduced in aged knees due to decreased VEGF-C/VEGFR3 signaling. VEGF-C treatment attenuates osteoarthritic joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR3 signaling represent novel physio-pathological mechanisms and therapeutic targets for age-related osteoarthritis.
