Lubricin function in articulating joints

描述（由申请人提供）：软骨表面及其周围滑膜的完整性影响关节的稳态和长期功能。这是一个有竞争力的更新申请，以继续我们对分泌蛋白润滑素（由基因PRG 4编码）的研究，该蛋白由浅区软骨细胞和B型滑膜细胞表达。我们和其他研究人员已经表明，润滑素是至关重要的保护和维护关节。我们已经证明润滑素可以防止关节软骨的机械磨损。遗传上缺乏润滑素的人类和小鼠会发生早熟的软骨衰竭和滑膜增生。我们已经观察到获得性改变的润滑素在常见的关节疾病，包括骨关节炎，类风湿性关节炎，创伤性关节损伤的患者。润滑素的这些获得性改变可以包括蛋白质丰度的变化、不同蛋白质剪接形式的表达以及特定的翻译后加工事件，如糖基化和蛋白质切割，这似乎对蛋白质的生物学和机械活性很重要。我们有三个总体研究目标。首先，我们希望精确地了解不同的润滑素剪接形式和翻译后修饰如何有助于蛋白质的不同细胞生物学，结构和生物物理特性。我们将通过研究从野生型动物、润滑素突变动物和转基因小鼠中回收的蛋白质和组织来实现这一目标，这些动物表达特定的润滑素剪接形式或润滑素蛋白质，这些蛋白质已被突变以阻止正常的翻译后加工。在目标二中，我们将开发一种可靠的和可重复的方法来诱导和测量整个关节的磨损。这将使我们能够了解润滑素如何防止体内磨损。重要的是要认识到，并非所有好的润滑剂都能防止磨损。因此，我们希望精确地定义润滑素如何防止磨损，以及它的哪些翻译后修饰对这种活性很重要。第三，我们希望将获得性润滑素改变与常见关节疾病联系起来，并确定这些润滑素改变是原因还是后果。我们将通过分析受常见关节疾病影响的患者队列以及获得性关节疾病（例如创伤性关节损伤和炎症性关节炎）的动物模型的滑液和血清来做到这一点。公共卫生相关性。本研究旨在了解分泌的蛋白质润滑素如何保护哺乳动物关节。遗传性缺乏润滑素会导致过早的关节衰竭。我们的初步数据表明，获得性改变的润滑素有助于关节疾病的进展，更常见的疾病影响关节，如骨关节炎，类风湿性关节炎，创伤性关节损伤的患者。我们将研究表达不同形式润滑素的小鼠，并研究正常和受损关节患者的生物样本，以开始将润滑素变化与人类关节健康联系起来。

DESCRIPTION (provided by applicant): The integrity of the cartilage surface and its surrounding synovium affects the homeostasis and long-term function of an articulating joint. This is a competitive renewal application to continue our studies of the secreted protein lubricin (encoded by the gene PRG4), which is expressed by superficial zone chondrocytes and type B synoviocytes. We and other investigators have shown that lubricin is critically important in the protection and maintenance of articulating joints. We have demonstrated that lubricin prevents mechanical wear of articular cartilage. Humans and mice that genetically lack lubricin develop precocious cartilage failure and synovial hyperplasia. We have observed acquired alterations of lubricin in patients with common joint diseases, including osteoarthritis, rheumatoid arthritis, and traumatic joint injury. These acquired alterations of lubricin can include changes in protein abundance, the expression of different protein splice-forms, and specific post-translational processing events, such as glycosylation and protein cleavage, which appear to be important to the protein's biological and mechanical activities. We have three overall research goals. First, we want to understand precisely how the different lubricin splice-forms and post-translational modifications contribute to the protein's diverse cell biologic, structural, and biophysical properties. We will accomplish this by studying protein and tissue recovered from wild-type animals, lubricin-mutant animals, and transgenic mice that express specific lubricin splice-forms or lubricin proteins that have been mutated to prevent normal post-translational processing. In aim two we will develop a reliable and reproducible methodology for inducing and measuring wear in whole joints. This will enable us to understand how lubricin prevents wear in vivo. It is important to appreciate that not all good lubricants prevent wear. Therefore, we want to precisely define how lubricin prevents wear and which of its post-translational modifications are important to this activity. Third, we want to correlate acquired alterations of lubricin with common diseases of joints and determine whether these lubricin alterations are causes or consequences. We will do this by analyzing synovial fluid and serum from cohorts of patients affected by common joint diseases and from animal models of acquired joint disease, such as traumatic joint injury and inflammatory arthritis. PUBLIC HEALTH RELEVANCE. This research aims to understand how the secreted protein lubricin protects mammalian joints. Genetic absence of lubricin cause precocious joint failure. Our preliminary data suggest that acquired alterations of lubricin contribute to the progression of joint disease in patients with more common diseases affecting joints, such as osteoarthritis, rheumatoid arthritis, and traumatic joint injury. We will study mice that express different forms of lubricin and also study biologic samples from patients with normal and damaged joints to begin correlating lubricin variation with human joint health.