Beta-Catenin Signaling and Pathogenesis of Osteoarthritis

β-连环蛋白信号传导和骨关节炎的发病机制

• 批准号: 7884592
• 负责人: DI CHEN
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884592
• 关键词: Address; Adult; Breeding; Cartilage; Chondrocytes; Degenerative polyarthritis; Development; Disease; Exons; Extracellular Matrix; Family member; Functional disorder; Gene Deletion; Gene Targeting; Genes; Genetic; Genetic Recombination; Growth Factor; Hip Osteoarthritis; Human Genetics; Incidence; Injury; Lead; Ligands; Mechanics; Mediating; Mediator of activation protein; Meniscus structure of joint; Modeling; Molecular Biology; Molecular Genetics; Morphology; Mus; Mutation; Pathogenesis; Patients; Phenotype; Play; Predisposition; Reporting; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Staging; Structure; Tamoxifen; Testing; Tissues; Transgenic Mice; Woman; age related; articular cartilage; beta catenin; cartilage cell; cell type; collagenase 3; frizzled related protein-3; genetic association; inhibitor/antagonist; joint injury; mouse model; novel; public health relevance; receptor

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. The articular chondrocyte is the only cell type in articular cartilage and these cells are responsible for maintaining the appropriate structure and function of the articular cartilage tissue. The function of articular chondrocytes is regulated by a variety of growth factors, including Wnt family members. Recent human genetic studies demonstrate that patients with a mutation (Arg324Gly substitution) in the secreted frizzled-related protein 3 (sFRP3), a Wnt signaling inhibitor, have a predisposition for the development of OA. It is also known that the mutation of sFRP3 causes activation of ¿-catenin signaling. These findings suggest that the canonical Wnt/¿-catenin signaling pathway may play a critical role during the development of OA. However, direct genetic and molecular evidence for the role of ¿-catenin in the development of OA has not been reported before. In preliminary studies, we demonstrated that ¿-catenin conditional activation (cAct) mice developed a severe OA-like phenotype. We also found that meniscus injury and mechanical injury, which often lead to the development of OA, activate canonical Wnt/¿-catenin signaling in articular chondrocytes. The underlying hypotheses of this proposal are that 1) canonical Wnt/¿-catenin signaling plays a key role and is required for sensing changes in meniscus injury and mechanical injury in articular chondrocytes and its abnormal activation will lead to the development of an OA-like phenotype; and 2) Bmp2 and Mmp13 are key downstream target genes of ¿-catenin signaling in articular chondrocytes and deletion of these genes will significantly reverse the OA-like phenotype observed in ¿-catenin cAct mice. In Specific Aim 1, we will analyze ¿-catenin cAct mice and determine the age-dependent OA-like phenotype in adult ¿-catenin cAct mice. Changes in articular cartilage structure and morphology and articular chondrocyte function will be examined in 3-, 6-, 9-, and 12-month-old ¿-catenin cAct mice. In addition, we will also determine if adult ¿-catenin cAct mice are more susceptible to chemically- or joint injury-induced OA. In Specific Aim 2, we will determine the role of meniscus injury or mechanical injury in activation of ¿-catenin signaling and the development of OA. We will determine if activation of the canonical Wnt/¿-catenin signaling is required for the meniscus injury- or mechanical injury-induced OA-like phenotype in articular chondrocytes. In Specific Aim 3, we will determine if Bmp2 and Mmp-13 are key downstream mediators of ¿-catenin signaling during the development of OA in adult ¿-catenin cAct mice. We will delete the Bmp2 or Mmp-13 gene in articular chondrocytes where the ¿-catenin gene is over expressed and determine if their deletion will significantly reverse the OA-like phenotype observed in ¿-catenin cAct mice. Our proposed studies will provide novel and definitive evidence about the role of ¿-catenin signaling in articular chondrocyte function and OA pathogenesis. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. Recent human genetic studies demonstrated that ¿-catenin signaling may play a key role in OA development. In the proposed studies, we will use molecular genetic approach and different mouse OA models to investigate the role of ¿-catenin in OA pathogenesis. The ¿-catenin gene will be specifically activated or deleted in articular chondrocytes in adult mice. Our studies will provide direct genetic evidence on the function of ¿-catenin in OA development.

描述（申请人提供）：骨关节炎（OA）是一种退行性关节疾病，对该疾病的发病机制知之甚少。关节软骨细胞是关节软骨中唯一的细胞类型，这些细胞负责维持关节软骨组织的适当结构和功能。关节软骨细胞的功能受到多种生长因子的调节，包括Wnt家族成员。最近的人类遗传学研究表明，分泌型卷曲相关蛋白 3 (sFRP3)（一种 Wnt 信号抑制剂）发生突变（Arg324Gly 取代）的患者容易患 OA。还已知 sFRP3 的突变会导致 ¿-连环蛋白信号的激活。这些发现表明经典的 Wnt/¿-catenin 信号通路可能在 OA 的发展过程中发挥关键作用。然而，之前尚未报道过β-连环蛋白在 OA 发展中的作用的直接遗传和分子证据。在初步研究中，我们证明 ¿-连环蛋白条件激活 (cAct) 小鼠出现了严重的 OA 样表型。我们还发现，半月板损伤和机械损伤通常会导致 OA 的发生，并激活关节软骨细胞中的经典 Wnt/¿-连环蛋白信号传导。该提议的基本假设是：1）经典的Wnt/¿-连环蛋白信号传导起着关键作用，是感知关节软骨细胞半月板损伤和机械损伤变化所必需的，其异常激活将导致OA样表型的发展； 2) Bmp2 和 Mmp13 是关节软骨细胞中 ¿-catenin 信号传导的关键下游靶基因，删除这些基因将显着逆转在 ¿-catenin cAct 小鼠中观察到的 OA 样表型。在具体目标 1 中，我们将分析 ¿-catenin cAct 小鼠并确定成年 ¿-catenin cAct 小鼠中年龄依赖性的 OA 样表型。将在 3、6、9 和 12 个月大的 ¿-catenin cAct 小鼠中检查关节软骨结构和形态以及关节软骨细胞功能的变化。此外，我们还将确定成年 ¿-catenin cAct 小鼠是否更容易受到化学损伤或关节损伤引起的 OA。在具体目标 2 中，我们将确定半月板损伤或机械损伤在 ¿-连环蛋白信号传导激活和 OA 发展中的作用。我们将确定半月板损伤或机械损伤诱导的关节软骨细胞中的 OA 样表型是否需要激活经典的 Wnt/¿-连环蛋白信号传导。在具体目标 3 中，我们将确定 Bmp2 和 Mmp-13 是否是成年 ¿-catenin cAct 小鼠 OA 发育过程中 ¿-catenin 信号传导的关键下游介质。我们将删除 ¿-catenin 基因过度表达的关节软骨细胞中的 Bmp2 或 Mmp-13 基因，并确定它们的删除是否会显着逆转 ¿-catenin cAct 小鼠中观察到的 OA 样表型。我们提出的研究将为 ¿-catenin 信号在关节软骨细胞功能和 OA 发病机制中的作用提供新颖且明确的证据。 公众健康相关性：骨关节炎 (OA) 是一种退行性关节疾病，人们对这种疾病的机制知之甚少。最近的人类遗传学研究表明，¿-连环蛋白信号传导可能在 OA 发展中发挥关键作用。在拟议的研究中，我们将使用分子遗传学方法和不同的小鼠 OA 模型来研究 ¿-catenin 在 OA 发病机制中的作用。成年小鼠关节软骨细胞中的 ¿-连环蛋白基因将被特异性激活或删除。我们的研究将为 ¿-连环蛋白在 OA 发展中的功能提供直接的遗传证据。