Pain Mechanisms of Knee Joint Osteoarthritis

描述（由申请人提供）：患有持续性膝关节疼痛的患者通常有软骨变性，损伤膝关节区域的滑膜、半月板和软骨下骨的结构和形态改变。骨关节炎是导致肌肉骨骼相关疼痛、心理困扰、生活质量受损和惊人的社会经济成本的主要原因（仅在美国每年估计就有1000亿美元）。目前，对这种常见疾病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，疼痛来源和受影响的细胞途径）尚未确定。为了研究背痛的病因并评估可能的临床干预机会，我们将通过使用代表性工具研究导致膝关节骨关节炎及其症状，膝关节疼痛的特定信号通路：1)建立OA动物模型模型，促进行为疼痛评估，研究疼痛机制；2)通过转基因小鼠了解膝关节骨性关节炎诱发的病理生理伤害感受通路；3)研究膝关节骨性关节炎引起的外周（背根神经节）和中枢（脊髓背角）反应以及神经胶质激活在慢性膝关节骨性关节炎疼痛中的作用。我们的研究可能揭示了骨性关节炎中受损的伤害性通路，并可能揭示通过神经源性衰减阻止软骨的进行性破坏，从而减轻脊柱水平的骨性关节炎疼痛确实对关节有益。这些研究的成功完成将证明，对PKC轴的有效控制不仅可以保护周围膝关节组织免受进一步退变，还可以缓解其临床衰弱症状，疼痛，这对广大患者的生活质量产生深远的影响。

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.