Investigating the Role of Sclerostin in Calcific Aortic Valve Disease

摘要 最近针对硬化素蛋白的单抗Romosozumab的临床试验表明，它可以 在降低骨质疏松症患者的骨折风险方面非常有效。然而，心血管副作用 一直是FDA批准该药物的主要障碍，并可能阻碍其在临床疾病中的采用 管理层。尽管最初认为硬化素只在骨骼中表达，但最近的研究 已经证明它在心血管组织、细胞和疾病中表达。相关研究流转 硬化素与心血管疾病的关系一直令人困惑。对硬化素作用机制的研究很少。 心血管疾病已经发表，但还没有人研究这种蛋白质在主动脉瓣健康中的作用 和疾病，尽管在患病的瓣膜中发现了这种蛋白质。钙化性主动脉瓣病(CAVD)是 心脏瓣膜病是最常见的疾病，在老龄化人群中越来越普遍。这是一个 臭名昭著的难以研究和治疗的疾病，每年导致大约15,000人死亡 北美。CAVD的发病机制以纤维钙化病变的逐渐积聚为特征 顺应性降低，难以将血液输送到体循环。无瓣膜置换术，CAVD 会通过心力衰竭导致死亡。迫切需要了解这一现象的分子病理生理学。 以开发有效的药物。我们实验室的初步结果表明硬化素是 在小鼠CAVD模型的发展过程中是必要的。此外，瓣膜间质细胞转化为疾病。 在体外用该蛋白处理时的表型。我们假设硬化素是CAVD的驱动因素 活化对RANKL-NF-κB信号通路的刺激导致纤维化和营养不良钙化 瓣膜间质细胞。这项建议的目标是更好地了解硬化素在CAVD中的作用并评估 它作为药理靶点的潜力。这项研究提出了两个主要目标：1)多尺度分子 SOST基因突变小鼠CAVD表型的特征2)心脏瓣膜病的前期调查 硬化素封闭治疗绝经后骨质疏松症的临床模拟。这项研究将是第一个确定 硬化素在主动脉瓣健康和疾病中的分子机制。深入分析遗传和 药物降低硬化素信号将提供对观察到的副作用的洞察 骨质疏松症的治疗以及治疗CAVD的潜力。

Abstract Recent clinical trials for Romosozumab, a monoclonal antibody targeting the protein sclerostin, have shown it to be highly effective in reducing fracture risk in patients with osteoporosis. However, cardiovascular side effects have been a major roadblock in FDA approval of the drug and may hinder its adoption in clinical disease management. Although it was originally believed sclerostin was only expressed in the skeleton, recent studies have demonstrated its expression in cardiovascular tissue, cells, and disease. Research correlating circulating sclerostin to cardiovascular disease has been confounding. Very few studies of the mechanism of sclerostin in cardiovascular disease have been published, and none have examined the protein’s role in aortic valve health and disease, despite the protein being discovered in diseased valves. Calcific aortic valve disease (CAVD) is the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in North America. Pathogenesis of CAVD is characterized by gradual accumulation of fibrocalcific lesions resulting in reduced compliance and difficulty pumping blood to systemic circulation. Without valve replacement, CAVD can lead to death via heart failure. There is an acute need to unravel the molecular pathophysiology of this disease in order to develop efficacious pharmaceuticals. Preliminary results from our lab indicate sclerostin is necessary in the development of CAVD in a mouse model. Additionally, valve interstitial cells shift to a disease phenotype when treated with the protein in vitro. We hypothesize sclerostin is a driver of CAVD through its stimulation of the RANKL-NFκB signaling pathway leading to fibrosis and dystrophic calcification by activated valve interstitial cells. The goal of this proposal is to better understand the role of sclerostin in CAVD and assess its potential as a pharmacological target. This study presents two primary aims: 1) multiscale molecular characterization of the CAVD phenotype of Sost genetic mutant mice 2) investigation of valve disease in a pre- clinical analogue of sclerostin blocking in post-menopausal osteoporosis. This study will be the first to identify the molecular mechanism of sclerostin in aortic valve health and disease. Intensive analysis of genetic and pharmacological reduction of sclerostin signaling will provide insight into the side effects observed in osteoporosis treatment as well as potential for treatment of CAVD.