Impact Damage, Apoptosis, and Early Osteoarthritis

描述（申请人的逐字记录）：健康平衡的破坏 生物力学环境和软骨结构之间的联系被认为 引发骨关节炎（OA）的发病机制。细胞凋亡可能是一个早期的 这一中断的后果。一个长期目标是确定和 了解发病初期软骨的变化。 这种认识是早期干预和预防艾滋病的先决条件。 在人类痛苦和经济损失方面，这种疾病使社会付出了巨大的代价。 在体内模型中，犬髋关节发育不良总是伴随着 OA提供了一个独特的机会，可以很早就看到自发的 （非手术）OA模型。体外模型，它使用冲击损伤， 模拟疾病过程的早期选择方面，将有助于解剖 发病机制。基于一个坚实的信息体， 这些模型，文献中报道的观察结果，以及令人兴奋的初步结果， 数据，假设关节软骨的冲击负荷水平 足以在损伤部位引起基质损伤和细胞死亡 释放细胞间信号，放射状传播凋亡波， 横向穿过软骨如果这种凋亡不能通过 正常和适当的检查和平衡内的软骨，它会 有助于软骨退化的特点， OA的发病机制。具体目标是解决以下问题：（1）为什么细胞 死亡在冲击载荷软骨内扩散， 损坏？(2a)细胞死亡在引发基质退化中有多重要 以及OA发病机制的其他特征性变化;及（2b） 相反，软骨环境是否能够阻止或延迟 细胞死亡的决定更能抵抗骨关节炎的发展 变更？为了回答这些问题，我们将对核心造成冲击破坏 软骨组织所涉及的信号因子的作用，以及 细胞死亡的第二波的性质，无论是凋亡，坏死，或 两者都将被定义。细胞死亡的同时， 将确定OA标志物并尝试抑制基质损伤 通过抑制细胞凋亡。我们将选择高风险和低风险的狗， OA。将检查病变好发区域的细胞死亡， 潜在的细胞死亡抑制剂，以及死亡信号将被视为 for.我们的期望是，通过交织细胞死亡的信息， 和软骨退化的研究， 关于OA发病机制最早阶段的重要新信息 会出现。

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.