Synovial lymphatics and osteoarthritis in aging

项目总结/文摘

Project Summary/Abstract Osteoarthritis (OA) affects ~35M people in the US and ~250M world-wide, but there is no effective therapy. OA is characterized by cartilage loss, synovial inflammation and subchondral bone remodeling, associated with the accumulation of numerous catabolic mediators and inflammatory cells in the synovial space. How these factors are cleared and if the “clearance” process contributes to the pathogenesis of OA is unknown. Using imaging tools that we developed in past 10 years, we identified a Synovial Lymphatic System (SLS) in mouse joints, the function of which is impaired in joints of mice with age-related OA. Thus, strategies to improve lymphatic function may benefit OA patients. In this application, we hypothesize that 1) aged joints have impaired SLS function and VEGFR3-mediated signaling, accompanied by reduced VEGF-C expression and elevated VEGFR3 degradation; 2) RANKL promotes ubiquitination and lysosomal degradation of VEGFR3 in LECs; and 3) the combination of VEGF-C and agents preventing VEGFR3 degradation improves the SLS and attenuates the development of OA during aging. We will use an age-related OA mouse model to test our hypotheses. In Aim 1, we will determine if the SLS becomes defective during aging and causes OA tissue damage, associated with reduced VEGFR3-mediated signaling in lymphatic endothelial cells. In Aim 2, we will determine the molecular mechanisms whereby VEGFR3 is degraded in aging joints and if a combination of VEGF-C and the inhibition of VEGFR3 degradation prevent OA in aging mice. The results of our study will establish a role for SLS dysfunction in the pathogenesis of OA, and augmentation of SLS functions could be a promising therapeutic approach to prevent or delay age-associated joint damage. This will provide preclinical evidence for agents targeting lymphatic vessels as a potential therapeutic strategy for OA in aging.