Pain Mechanisms of Knee Joint Osteoarthritis

描述(申请人提供)：患有持续性膝关节疼痛的患者通常有软骨变性，在受损的膝关节区域滑膜、半月板和软骨下骨的结构和形态发生变化。骨关节炎是肌肉骨骼相关疼痛、心理困扰、生活质量受损和惊人的社会经济成本(仅在美国每年估计就有1000亿美元)的主要原因。目前，对于这种常见的疾病还没有有效的治疗方法。膝关节疼痛的缓解受到阻碍，因为引起疼痛的机制(例如，痛源和受影响的细胞通路)尚未建立。为了研究背痛的病因并评估可能的临床干预机会，我们将利用具有代表性的工具：1)建立有助于研究疼痛机制的行为疼痛评估的OA动物模型，2)建立转基因小鼠以了解膝关节骨关节炎引起的病理生理伤害性反应，3)研究膝关节骨性关节炎对周围(背根节)和中枢(脊髓背角)的反应以及胶质细胞激活在慢性膝关节骨性关节炎中的作用。我们的研究可能揭示在骨性关节炎条件下损伤的伤害性通路，并可能揭示在脊柱水平减轻骨性关节炎疼痛确实是有益的，因为它通过神经源性衰减阻止了软骨的进行性破坏。这些研究的成功完成将确立，有效控制PKC轴不仅可以保护周围膝关节组织免受进一步退化，还可以缓解其临床上令人衰弱的症状-疼痛，该症状对生活质量或广大患者产生深远影响。 公共卫生相关性：这项应用提供了一个独特的机会，通过结合转基因小鼠和已建立的可接受行为疼痛测试的转换动物模型来研究骨关节炎启动的伤害性通路，这些动物模型为这一高度研究不足的领域的快速发展奠定了基础。我们的结果将发现一种新的伤害性通路和分子机制，这是临床方案无法解决的，并将为骨关节炎引起的膝关节疼痛建立新的实验途径和新的研究方向。

DESCRIPTION (provided by applicant): Patients suffering from persistent knee joint pain typically have cartilage degeneration with structural and morphological changes in synovium, meniscus and subchondral bone at the damage knee joint region. Osteoarthritis is a leading cause of musculoskeletal-associated pain, psychological distress, impaired quality of life, and staggering socio-economic costs (estimated at $100 billion per year in the US alone). Currently, there is no effective treatment for this common affliction. Relief of knee joint pain is hampered because causative mechanisms (e.g., the pain source and affected cellular pathways) have not yet been established. To investigate the etiology of back pain and assess opportunities for possible clinical intervention, we will investigate specific signaling pathways leading to knee joit osteoarthritis and its symptom, knee pain by using representative tools: 1) established OA animal model model for facilitating behavioral pain assessments that allow us to investigate pain mechanisms, 2) genetically modified mice to understand pathophysiological nociceptive pathway evoked by knee osteoarthritis, and 3) investigation of peripheral (dorsal root ganglions) and central (spinal dorsal horn) responses by knee joint OA and roles of glial activation in chronic knee joint osteoarthritic pain. Our studies may uncover the nociceptive pathway that is impaired in OA condition, and may reveal that alleviation of OA pain at the spinal level is indeed beneficial to the joints by arresting progressive cartilage destruction through neurogenic attenuation. Successful completion of these studies will establish that effective controls of the PKC axis not only protects peripheral knee joint tissues from further degeneration, but also relieves its clinically debilitating symptom, pain, that profoundly impacts on the quality of life or a vast number of patients. PUBLIC HEALTH RELEVANCE: This application provides a unique opportunity to study nociceptive pathway initiated by osteoarthritis by combining genetically modified mice and established translational animal models that are amenable to behavioral pain tests that have set the stage for rapid advances in this highly under-studied area. Our results will discover a novel nociceptive pathway and molecular mechanisms that cannot be addressed by clinical protocols in humans, and will establish new experimental avenues and novel research directions for osteoarthritis-caused knee joint pain.