Synovial lymphatics and osteoarthritis in aging

项目概要/摘要 骨关节炎（OA）影响美国约3500万人，全球约2.5亿人，但没有有效的治疗方法。OA 其特征是软骨损失，滑膜炎症和软骨下骨重塑，与 大量分解代谢介质和炎性细胞在滑膜空间中的积聚。这些因素如何 清除，如果“清除”过程有助于OA的发病机制是未知的。使用成像 我们在过去10年中开发的工具，我们确定了小鼠关节中的滑膜淋巴系统（SLS）， 其功能在患有年龄相关性OA的小鼠的关节中受损。因此，改善淋巴系统的策略 功能可能有益于OA患者。在本申请中，我们假设1）老年关节的SLS受损 功能和VEGFR 3介导的信号传导，伴随着VEGF-C表达减少和VEGF-C表达升高， 2）RANKL促进LEC中VEGFR 3的泛素化和溶酶体降解;和 3)VEGF-C和防止VEGFR 3降解的试剂的组合改善SLS并减弱 OA在衰老过程中的发展。我们将使用年龄相关的OA小鼠模型来测试我们的假设。在 目的1，我们将确定SLS是否在老化过程中出现缺陷并导致OA组织损伤， 淋巴管内皮细胞中VEGFR 3介导的信号传导减少。在目标2中，我们将确定 VEGFR 3在老化关节中降解的分子机制，以及如果VEGF-C和 抑制VEGFR 3降解可预防衰老小鼠中OA。我们的研究结果将建立一个角色， SLS功能障碍在OA发病机制中的作用，增强SLS功能可能是一种有前途的 预防或延缓与年龄相关的关节损伤的治疗方法。这将提供临床前证据 针对淋巴管的药物作为衰老中OA的潜在治疗策略。

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.