Impact Damage, Apoptosis, and Early Osteoarthritis

冲击损伤、细胞凋亡和早期骨关节炎

基本信息

批准号：
6318974
负责人：
NANCY I BURTON-WURSTER
金额：
$ 27.83万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2004-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (Verbatim from the Applicant): A disruption in the healthy balance between the biomechanical environment and the cartilage structure is thought to initiate the pathogenesis of osteoarthritis (OA). Apoptosis may be an early consequence of this disruption. A long-term objective is to identify and understand the cartilage changes which occur at the initiation of pathogenesis. This understanding is prerequisite for early intervention and prevention of a disease that costs society much in terms of human suffering and economic loss. The in vivo model, in which canine hip dysplasia is invariably accompanied by OA, gives the unique opportunity to look very early at changes in a spontaneous (non-surgical) model of OA. The in vitro model, which uses impact damage to mimic select early aspects of the disease process, will aid in dissection of the mechanisms of pathogenesis. Grounded in a solid body of information about these models, observations reported in the literature, and exciting preliminary data, the hypothesis is that a level of impact loading of articular cartilage sufficient to cause both matrix damage and cell death at the site of injury releases intercellular signals which propagate a wave of apoptosis radially and transversely through the cartilage. If this apoptosis cannot be prevented by normal and appropriate checks and balances within the cartilage, it will contribute to the cartilage degeneration characteristic of the early pathogenesis of OA. The Specific Aims address the questions: (1) why does cell death spread within impact-loaded cartilage beyond the site of original damage?; (2a) how important is cell death in triggering the matrix degeneration and other changes characteristic of the pathogenesis of OA?; and (2b) conversely, will a cartilage environment capable of preventing or delaying a cell's decision to die be more resistant to development of osteoarthritic changes? To answer these questions, we will inflict impact damage in the cores of explanted cartilage. The role of the signaling factors involved, as well as the nature of the secondary wave of cell death, whether apoptosis, necrosis, or both will be defined. The coincidence of cell death and the appearance of other markers of OA will be determined and an attempt made to inhibit matrix damage by inhibiting apoptosis. We will select dogs at high and low risk of developing OA. Cell death at the area of lesion predilection will be examined and potential inhibitors of cell death, as well as death signals will be looked for. The expectation is that by interdigitating information about cell death and cartilage degeneration from these unique in vivo and in vitro models, important new information about the earliest stages in the pathogenesis of OA will emerge.

描述（申请人逐字记录）：健康平衡被破坏生物力学环境和软骨结构之间的关系被认为是引发骨关节炎（OA）的发病机制。细胞凋亡可能是早期这种破坏的后果。长期目标是确定并了解发病机制开始时发生的软骨变化。这种理解是早期干预和预防的先决条件疾病给社会造成巨大的人类痛苦和经济损失。在体内模型中，犬髋关节发育不良总是伴有 OA 提供了独特的机会，可以很早就观察自发的变化 OA（非手术）模型。体外模型，利用冲击损伤模仿选择疾病过程的早期方面，将有助于解剖发病机制。以可靠的信息为基础这些模型、文献中报告的观察结果以及令人兴奋的初步结果数据，假设关节软骨的冲击载荷水平足以引起损伤部位的基质损伤和细胞死亡释放细胞间信号，径向传播细胞凋亡波，横向穿过软骨。如果这种细胞凋亡不能被阻止软骨内正常且适当的制衡，它将导致早期软骨退化特征 OA 的发病机制。具体目标解决了以下问题：（1）为什么细胞死亡在受冲击载荷的软骨内扩散到原始部位之外损害？; (2a) 细胞死亡对于引发基质变性有多重要以及 OA 发病机制的其他特征变化？和 (2b) 相反，软骨环境是否能够预防或延迟细胞死亡的决定对骨关节炎的发展具有更强的抵抗力变化？为了回答这些问题，我们将对核心造成冲击损坏的外植软骨。所涉及的信号因子的作用以及第二波细胞死亡的性质，无论是凋亡、坏死还是两者都将被定义。细胞死亡与其他细胞出现同时发生将确定 OA 标记物并尝试抑制基质损伤通过抑制细胞凋亡。我们将选择患有高风险和低风险的狗办公自动化。将检查病变好发区域的细胞死亡情况并将研究细胞死亡的潜在抑制剂以及死亡信号为了。期望通过交叉有关细胞死亡的信息以及这些独特的体内和体外模型的软骨退化，关于 OA 发病机制最早阶段的重要新信息将会出现。