Pathogenesis of Osteoarthritis in Col2a1 Mutant Mice

（申请人提供）：申请？的主要目标是 开发骨关节炎（OA）的动物模型，以了解 关节炎发生的组织病理学和机制 软骨病以OA形式的滑膜关节组织退化是 是人类慢性残疾的主要原因之一。在大多数情况下， OA是特发性的，因此，迫切需要动物模型用于研究。 了解所涉及的机制，并为 开发用于治疗和预防的药物和基因疗法 这种骨骼疾病。其中一类蛋白质在 关节软骨的结构和功能，三螺旋胶原， 似乎参与了这种疾病的发病机制，特别是那些 与轻度软骨发育不良相关的遗传性OA类型。不相称 短肢畸形（Dmm）是小鼠中的一种半显性II型胶原（Col 2a 1）突变 在杂合子状态下会导致轻度侏儒症初步研究， 包括对6个月和9个月大的膝关节进行的小型组织学研究， 小鼠，也表明OA的存在。拟议研究的目的 是扩大这些初步研究， Dmm/+小鼠中OA的发展。光学显微镜的使用将允许 检查膝关节内的细胞变化以及非承重 不同年龄杂合小鼠的关节软骨。电子显微镜 将允许检查亚细胞和基质的变化， 观察组织学变化。免疫组织化学将允许记录 I型胶原蛋白的存在以及这种OA的出现 生物标志物如降解的胶原蛋白和降解的蛋白聚糖，以及 相应的金属蛋白酶与这种发病时间的关系 组织病理学变化。总体目标是建立Dmm/+小鼠， OA的动物模型，其中可以测试各种疗法以确定 是否能预防OA的发生或进展。

DESCRIPTION (provided by applicant): The application?s major objective is to develop an animal model for osteoarthritis (OA) to provide an understanding of the histopathology and mechanisms involved in the development of articular cartilage disease. Degeneration of synovial joint tissue in the form of OA is one of the leading causes of chronic disability in humans. For the most part, OA is idiopathic and, therefore, animal models are urgently needed for the understanding of the mechanisms involved and to lay the foundation for the development of drug and gene therapies used in the treatment and prevention of this skeletal disease. One class of proteins that plays an essential role in the structure and function of articular cartilage, triple helical collagen, appears to be involved in the pathogenesis of this disease, particularly those types of hereditary OA associated with mild chondrodysplasia. Disproportionate micromelia (Dmm) is a semidominant, type II collagen (Col2a1) mutation in mice that, in the heterozygous condition, causes mild dwarfism. Preliminary studies, including small histological studies on knee joints from 6- and 9-month-old mice, indicate the presence of OA as well. The purpose of the proposed research is to expand these preliminary studies to thoroughly characterize the development of OA in Dmm/+ mice. The use of light microscopy will permit examination of cellular changes within knee-joint as well as non-weight-bearing articular cartilages of various aged heterozygous mice. Electron microscopy will permit examination of subcellular and matrix changes in relation to the observed histological changes. Immunohistochemistry will allow documentation of the presence of type I collagen, as well as the appearance of such OA biomarkers as degraded collagen and degraded proteoglycan, and up-regulation of the corresponding metalloproteinases in relation to the time-of-onset of such histopathological changes. The overall objective is to establish Dmm/+ mice as an animal model of OA in which various therapies can be tested to determine whether they prevent OA initiation or progression.