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。表浅区软骨细胞的丢失和软骨表面的纤维化是骨关节炎的早期症状。内膜细胞增生和内膜下纤维化在类风湿性关节炎中是显著的，其中关节破坏部分由侵袭性和侵入性滑膜过度生长介导。本申请提出探索分泌蛋白润滑素（也称为巨核细胞刺激因子前体、浅区蛋白、弯曲趾关节病-髋内翻-心包炎综合征蛋白和蛋白聚糖4）在维持关节连接关节中的作用。这种蛋白质在关节内环境稳定中有几个重要作用，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。这种蛋白质的遗传缺陷导致常染色体隐性CACP综合征，其与早熟关节衰竭相关，并且这种蛋白质的获得性缺陷可能导致骨关节炎和类风湿性关节炎中的关节衰竭。由于润滑素是由表面软骨细胞和滑膜细胞合成并分泌到滑液中的蛋白质，我们推测它可能是治疗常见关节疾病的有用试剂或靶标。本申请具有四个主要目的：目的1）关于滑膜细胞的细胞生物学性质以及关节表面（椎板）的生物物理和结构性质来表征润滑素敲除小鼠。目的2）阐明润滑素中哪些结构域对其翻译后修饰和生物学特性（如蛋白质相互作用、润滑作用和细胞生长调节）起重要作用。目的3）建立外源性调控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时间作用。目的4）研究CACP综合征和常见关节疾病（包括骨关节炎、类风湿性关节炎和创伤性关节损伤）患者滑液中润滑素功能的遗传性和获得性改变。

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.