Synovial lymphatics and osteoarthritis in aging

项目摘要/摘要 骨关节炎(OA)影响着美国约3500万人和全球约2.5亿人，但目前还没有有效的治疗方法。办公自动化 以软骨丢失、滑膜炎症和软骨下骨重塑为特征，与 大量分解代谢介质和炎性细胞聚集在滑膜间隙。这些因素是如何 目前尚不清楚“清除”过程是否参与了骨关节炎的发病机制。使用成像 我们在过去10年中开发的工具，我们在小鼠关节中发现了一个滑膜淋巴系统(SLS)， 在老年性骨性关节炎小鼠的关节中，其功能受损。因此，改善淋巴循环的策略 功能可能使骨性关节炎患者受益。在这个应用中，我们假设1)老化的关节损害了SLS 功能和VEGFR3介导的信号转导，伴随着VEGF-C表达的降低和表达的升高 VEGFR3的降解；2)RANKL促进晶状体上皮细胞中VEGFR3的泛素化和溶酶体降解； 3)联合应用血管内皮生长因子-C和抑制血管内皮生长因子受体3降解的药物可改善SLS，减弱SLS 衰老过程中骨性关节炎的发展。我们将使用与年龄相关的骨性关节炎小鼠模型来检验我们的假设。在……里面 目标1，我们将确定SLS是否在老化过程中变得有缺陷并导致骨关节炎组织损伤，相关 淋巴管内皮细胞中VEGFR3介导的信号转导减少。在目标2中，我们将确定 VEGFR3在老化关节中降解的分子机制以及如果VEGF-C和 抑制VEGFR3的降解可预防衰老小鼠的骨性关节炎。我们的研究结果将为 SLS功能障碍在骨性关节炎发病机制中的作用，SLS功能的增强可能是一个很有前途的研究方向 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 以淋巴管为靶点的药物作为老年性骨性关节炎的潜在治疗策略。

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.