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：
6632769
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 2005-04-30
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（申请人的逐字病）：健康平衡的中断在生物力学环境和软骨结构之间被认为是启动骨关节炎（OA）的发病机理。凋亡可能是早期的这种破坏的结果。一个长期目标是确定和了解发病机理启动时发生的软骨变化。这种理解是早期干预和预防的先决条件在人类苦难和经济损失方面，使社会损失的疾病很大。体内模型，其中犬髋关节发育不良总是伴随着 OA，提供了独特的机会，可以很早地观察自发的变化 OA的（非手术）模型。使用影响损害的体外模型模仿疾病过程的精选早期方面，将有助于解剖发病机理的机制。基于关于这些模型，文献报道的观察以及令人兴奋的初步数据，假设是关节软骨的冲击负荷水平足以在受伤部位引起基质损伤和细胞死亡释放细胞间信号，该信号在径向传播一波凋亡和通过软骨横向。如果无法阻止这种凋亡软骨内的正常和适当的检查和平衡，它将有助于早期的软骨变性特征 OA的发病机理。具体目的解决了问题：（1）为什么要细胞死亡在撞击负载的软骨内蔓延到原始地点以外损害？; （2a）细胞死亡在触发基质变性中的重要性以及OA的发病机理的其他变化特征；和（2b）相反，软骨环境将能够预防或延迟 Cell的死亡决定对骨关节炎的发展更具抵抗力变化？要回答这些问题，我们将对核心造成影响损害外植的软骨。信号因素的作用以及细胞死亡的次要波的性质，无论是凋亡，坏死还是两者都将定义。细胞死亡的巧合和其他将确定OA的标记，并尝试抑制矩阵损坏通过抑制凋亡。我们将选择发育的高风险和低风险的狗 OA。将检查病变偏好区域的细胞死亡，并将检查可能会看到细胞死亡的潜在抑制剂以及死亡信号为了。期望是通过互换有关细胞死亡的信息这些独特的体内和体外模型的软骨变性，有关OA发病机理中最早阶段的重要新信息会出现。