Lubricin Function in Articulating Joints

描述(申请人提供)：软骨表面及其周围滑膜的完整性影响关节的动态平衡和长期功能。浅表区软骨细胞的丧失和软骨表面的纤颤是骨关节炎的早期迹象。类风湿性关节炎的关节破坏部分是由侵袭性和侵袭性滑膜过度生长引起的，其显著特点是内膜细胞增生和内膜下纤维化。本研究拟探讨分泌型蛋白润滑素(又称巨核细胞刺激因子前体、浅区蛋白、喜指关节病-髋关节内翻-心包炎综合征蛋白、蛋白多糖4)在关节维持中的作用。该蛋白在关节动态平衡中有几个重要的作用，包括关节表面的保护和边界润滑，以及调节内膜细胞的生长。该蛋白的遗传缺陷可导致常染色体隐性遗传性CACP综合征，常染色体隐性遗传性CACP综合征与早熟关节衰竭有关，而该蛋白的获得性缺失可能导致骨关节炎和类风湿关节炎的关节衰竭。由于润滑素是一种由表面软骨细胞和合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药物或靶点。这项应用有四个主要目的：目的1)从滑膜细胞的细胞生物学特性以及关节表面(光滑板)的生物物理和结构特性方面表征润滑素基因敲除小鼠。目的2)描述润滑剂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具有重要作用。目的3)建立一种可外源调控润滑素表达的转基因小鼠。这将使我们能够探索润滑剂在关节发育和动态平衡中的暂时作用。目的4)明确CACP综合征和骨关节炎、类风湿性关节炎、创伤性关节损伤等关节常见病患者滑液中润滑剂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.