Wnt7a-Mediated Competence to Resist Osteoarthritis Progression

摘要：Wnt7a介导的抗骨关节炎进展能力 骨关节炎(OA)是一种高度流行且使人衰弱的疾病，目前尚无有效的治疗方法。办公自动化有 许多危险因素，如关节损伤和衰老。然而，许多具有这些风险因素的人不会发展成 或将其发展到较小的程度。对相同治疗的个体反应通常也是高度不同的， 阻碍在合理规模的人群中进行治疗测试。因此，迫切需要了解 骨性关节炎表现形式多样的基础。骨性关节炎的一个驱动因素被认为是局部炎症。 由于长期的炎症会引起关节的分解代谢变化，每个个体的抵抗能力 炎症可能与疾病的发展轨迹直接相关。确定哪些因素可提供 抵抗炎症的能力可能是阐明个人骨性关节炎进展原因的关键。 我们的长期目标是研究OA的发病机制，以提高其治疗水平。这笔赠款的目标是 调查未被勘探的人所赋予的抗炎和关节破坏的能力 WNT信号家族的分子(Wnt7a)。这一建议是基于我们的研究，该研究显示了一个引人注目的 人软骨中WNT7a基因与分解代谢基因的负指数关系 标本。当Wnt7a表达低于某一阈值时，样本几乎都是OA 背景，似乎WNT7a水平低意味着较高的骨关节炎风险。在这种情况下，WNT7a可能是一个关键因素 与办公自动化变异性有关。Wnt7a基因在正常条件下的异位表达对软骨的影响 基质水平，但强烈阻止实验性骨性关节炎的关节破坏，表明WNT7a提供了关节 具有一定的抵抗办公自动化的能力。因此，我们假设WNT7a在关节软骨中的水平 决定了每个人的抗炎能力和影响骨性关节炎的轨迹， 形成了办公自动化可变性的基础。这一假设将通过以下两个具体目的进行检验：1)调查 WNT7a是否改变了骨性关节炎的炎症过程及软骨丢失和关节破坏的轨迹 2)确定Wnt7a的下游途径和上游调控因子。我们将使用收益和损失 在小鼠骨性关节炎和人软骨标本上的功能探讨。这项研究的新颖性在于 Wnt7a作为个体骨关节炎抵抗能力因子的概念探讨 在办公自动化中的异质性，以及使用先进的成像技术来测试这些概念。这些研究 将确定Wnt7a在抑制长期炎症和退行性变化倾向方面的作用 在办公自动化中。此外，它还将确定增强或保存内源性WNT7a的基本机制 对软骨起到保护关节的作用。因此，这项工作将为办公自动化提供重要的机械论见解 进展及其变异性以及治疗这种疾病的策略的设计。

Abstract: Wnt7a-mediated competence to resist osteoarthritis progression Osteoarthritis (OA) is a highly prevalent and debilitating disease that currently has no effective therapy. OA has many risk factors, such as joint injury and aging. However, many people with these risk factors do not develop OA or develop it to a lesser extent. Individual responses to the same treatment are often also highly variable, hampering the testing of therapy in a reasonable-sized population. Thus, there is an urgent need to understand the basis for the diverse manifestations of OA. One driving factor of OA is proposed to be local inflammation. As prolonged inflammation elicits catabolic changes in the joint, the ability of each individual to resist inflammation could be directly linked to the trajectory of disease progression. Identifying factors that provide the competence to resist inflammation may be key to elucidating the cause of OA progression in individuals. Our long-term goal is to investigate OA pathogenesis to improve its treatment. The goal of this grant is to investigate the competence to resist inflammation and joint destruction conferred by an underexplored molecule (Wnt7a) from the Wnt signaling family. This proposal is based on our study that showed a striking negative-exponential relationship between Wnt7a and catabolic genes in individual human cartilage specimens. When Wnt7a expression was below a certain threshold, the samples were almost always of OA background, as if low levels of Wnt7a signify a higher risk of OA. In this way, Wnt7a may be a key factor associated with OA variability. Ectopic expression of Wnt7a under normal conditions did not impact cartilage matrix levels, but strongly halted joint destruction in experimental OA, suggesting that Wnt7a provided the joint with a certain ability to resist OA. Thus, we hypothesize that the level of Wnt7a within articular cartilage determines the competence against inflammation and impacts the trajectory of OA in each individual, forming the basis for OA variability. This hypothesis will be tested in two Specific Aims by 1) investigating whether Wnt7a alters the course of inflammation and the trajectory of cartilage loss and joint destruction in OA and 2) identifying downstream pathways and upstream regulators of Wnt7a. We will use gain- and loss-of function approaches on mouse OA and human cartilage specimens. The novelty of this study lies in the concept of Wnt7a as a competence factor for OA resistance in individuals to explore the mechanism of heterogeneity in OA, and in the use of advanced imaging technologies to test these concepts. These studies will define the role of Wnt7a in curtailing prolonged inflammation and the propensity for degenerative changes in OA. Furthermore, it will identify fundamental mechanisms for enhancing or preserving endogenous Wnt7a function in cartilage for joint protection. Thus, this work will provide important mechanistic insights into OA progression and its variability and the design of strategies to treat this disease.