Pain Mechanisms of Knee Joint Osteoarthritis

描述（由申请方提供）：持续性膝关节疼痛患者通常在膝关节损伤区域发生软骨退化，滑膜、半月板和软骨下骨发生结构和形态学变化。骨关节炎是肌肉系统相关疼痛、心理困扰、生活质量受损和惊人的社会经济成本（仅在美国估计每年就有1000亿美元）的主要原因。目前，对这种常见的痛苦没有有效的治疗方法。膝关节疼痛的缓解受到阻碍，因为致病机制（例如，疼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，我们将使用代表性工具研究导致膝关节骨性关节炎及其症状膝关节疼痛的特定信号通路：1）建立了用于促进行为疼痛评估的OA动物模型，使我们能够研究疼痛机制，2）遗传修饰小鼠以了解膝骨关节炎诱发的病理生理伤害感受通路，（3）周边调查（背根神经节）和中枢（脊髓背角）的反应以及胶质细胞活化在慢性膝关节骨关节炎疼痛中的作用。我们的研究可能揭示OA条件下受损的伤害性通路，并可能揭示在脊柱水平缓解OA疼痛确实有益于关节，通过神经源性衰减阻止进行性软骨破坏。这些研究的成功完成将确定PKC轴的有效控制不仅保护外周膝关节组织免于进一步退化，而且还减轻其临床上使人衰弱的症状，疼痛，这对生活质量或大量患者产生深刻影响。 公共卫生相关性：该申请提供了一个独特的机会，通过结合基因修饰小鼠和建立的翻译动物模型，研究骨关节炎引发的伤害性通路，这些动物模型适合于行为疼痛测试，为这一高度欠研究的领域的快速发展奠定了基础。我们的研究结果将发现一个新的伤害性通路和分子机制，不能在人类的临床协议解决，并将建立新的实验途径和新的研究方向骨关节炎引起的膝关节疼痛。

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.