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。浅表带软骨细胞的丧失和软骨表面的颤动是骨关节炎的早期征兆。在类风湿关节炎中，关节破坏部分是由侵袭性和侵袭性滑膜过度生长介导的，内膜细胞增生和内膜下纤维化是显著的。本研究旨在探讨分泌蛋白润滑素（又称巨核细胞刺激因子前体、浅表带蛋白、喜树趾-关节病-髋关节变异性心包炎综合征蛋白、蛋白多糖4）在关节维持中的作用。这种蛋白在关节内稳态中有几个重要的作用，包括关节表面的保护和边界润滑，以及内膜细胞生长的调节。该蛋白的遗传缺陷导致常染色体隐性CACP综合征，该综合征与关节早衰有关，获得性缺乏该蛋白可能导致骨关节炎和类风湿性关节炎的关节衰竭。由于润滑素是一种由表面软骨细胞和滑膜细胞合成并分泌到滑膜液中的蛋白质，我们推测它可能是治疗常见关节疾病的有用药物或靶点。该应用程序有四个主要目的：目的1)表征润滑油敲除小鼠滑膜细胞的细胞生物学特性，以及关节表面（彩层）的生物物理和结构特性。目的2)描述润滑素中哪些结构域对其翻译后修饰和生物学特性（如蛋白质-蛋白质相互作用、润滑和细胞生长调节）至关重要。目的3)建立一种外源调节润滑素表达的转基因小鼠。这将使我们能够探索润滑素在关节发育和体内平衡中的作用。目的4)确定CACP综合征和常见关节疾病（包括骨关节炎、类风湿关节炎和创伤性关节损伤）患者滑液中润滑素功能的遗传和获得性改变。

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. The loss of superficial zone chondrocytes and fibrillation of the cartilage surface are early signs of osteoarthritis. Intimal cell hyperplasia and sub-intimal fibrosis is striking in rheumatoid arthritis where joint destruction is, in part, mediated by aggressive and invasive synovial overgrowth. This application proposes to explore the role of the secreted protein lubricin (also known as megakaryocyte stimulating factor precursor, superficial zone protein, camptodactyly-arthropathy-coxa vara-pericarditis syndrome protein, and proteoglycan 4) in the maintenance of articulating joints. This protein has several important roles in joint homeostasis, including the protection and boundary lubrication of articulating surfaces, and the regulation of intimal cell growth. Genetic deficiency of this protein causes the autosomal recessive CACP syndrome, which is associated with precocious joint failure, and acquired deficiency of this protein likely contributes to joint failure in osteoarthritis and rheumatoid arthritis. Since lubricin is a protein that is synthesized by surface chondrocytes and synviocytes and is secreted into the synovial fluid, we speculate that it may be a useful agent, or target, in the treatment of common joint disease. This application has four major aims: Aim 1) Characterize the lubricin knockout mouse with respect to cell biological properties of synoviocytes, and the biophysical and structural properties of the articular surface (lamina splendens). Aim 2) Delineate which domains in lubricin are important for its post-translational modification and biologic properties, such as protein-protein interactions, lubrication, and cell growth regulation. Aim 3) Create a transgenic mouse in which lubricin expression can be exogenously regulated. This will allow us to explore the temporal role of lubricin in joint development and homeostasis. Aim 4) Identify hereditary and acquired alterations of lubricin function within synovial fluid from patients with CACP syndrome and common diseases of joints including osteoarthritis, rheumatoid arthritis, and traumatic joint injury.