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内稳态和长期功能。这是一个竞争性的更新申请，以继续我们对分泌蛋白润滑素（由基因PRG4编码）的研究，它是由浅表带软骨细胞和B型滑膜细胞表达的。我们和其他研究人员已经表明，润滑剂对关节的保护和维护至关重要。我们已经证明，润滑剂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出现软骨早衰和滑膜增生。我们观察到常见关节疾病（包括骨关节炎、类风湿关节炎和创伤性关节损伤）患者获得性润滑素改变。这些获得性的润滑素改变可能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和机械活性很重要。我们有三个总体研究目标。首先，我们想要准确地了解不同的润滑蛋白剪接形式和翻译后修饰如何影响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恢复的蛋白质和组织来实现这一目标，这些小鼠表达特定的润滑素剪接形式或已经突变以阻止正常的翻译后加工的润滑素蛋白。在目标二，我们将开发一个可靠的和可重复的方法来诱导和测量整个关节的磨损。这将使我们了解润滑油是如何防止体内磨损的。重要的是要认识到并不是所有好的润滑剂都能防止磨损。因此，我们想精确地定义润滑油是如何防止磨损的，以及它的哪些转译后修饰对这种活动很重要。第三，我们希望将获得性润滑素的改变与常见的关节疾病联系起来，并确定这些润滑素的改变是原因还是后果。我们将通过分析来自常见关节疾病患者队列和获得性关节疾病（如创伤性关节损伤和炎症性关节炎）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蛋白润滑素是如何保护哺乳动物关节的。遗传缺乏润滑导致关节早衰。我们的初步数据表明，获得性润滑素的改变有助于关节疾病的进展，如骨关节炎、类风湿关节炎和创伤性关节损伤等常见关节疾病。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，以开始将润滑素变异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.