Osteoarthritis and Knee Joint Pain

摘要： 骨关节炎(OA)，通常被称为关节炎，导致关节疼痛，是最常见的慢性疾病之一 退伍军人的状况。事实上，退伍军人的情况比非退伍军人更糟糕；其中之一 每四名退伍军人中就有一名患有严重的关节炎，40岁以上的人患关节炎的可能性是退伍军人的两倍。 回到平民生活后患上关节炎。骨性关节炎症状、疼痛，是求医的关键原因 然而，目前还没有有效的方法来缓解骨性关节炎引起的疼痛。 尽管慢性骨性关节炎的严重疼痛对生活质量和医疗保健有重大的负面影响 管理，我们只很少了解疼痛的起源在骨性关节炎，分子机制推动 病理，以及有效治愈骨性关节炎的方法。许多情况下最终需要用关节置换 昂贵的假体和有限的功能寿命(~10年)可以进行第二次更换 这是必要的。这些因素既增加了治疗的总成本，也增加了相关发病率的风险。 值得注意的是，解决这种情况的手术程序通常不会导致无痛治愈。 我们的中心假设是Flt1(血管内皮生长因子受体-1)的激活是主要的 外周(感觉神经元)可塑性和中枢神经胶质细胞激活驱动关节痛传递 (血管内皮生长因子受体-2)是骨关节炎软骨退变的主要原因。 因此，FDA批准的小分子帕佐帕尼同时抑制Flt1和Flk1的进展 抗癌药物，将作为一种理想的骨关节炎疾病修改药物(OADMD)，立即减少关节 疼痛和逐渐的软骨再生。我们提议的研究结果将在办公自动化领域 研究向前迈出了一大步：在短期内，通过增加我们对原因的机械性理解 和进展，并通过开发有效和安全地治疗骨性关节炎和关节疼痛的新策略 在我们临床前的OA动物模型中；从长远来看，通过为临床试验提供测试的理论基础 帕佐帕尼治疗骨性关节炎患者。

ABSTRACT: Osteoarthritis (OA), commonly referred as arthritis, causing painful joints, is among the most common chronic conditions among veterans. Indeed, the condition is much worse among veterans than non-veterans; one of every four veterans lives with a serious arthritic condition and individuals over age 40 are twice as likely to develop arthritis after returning to civilian life. Osteoarthritic symptom, pain, is the key reason to seek medical assistance, yet there is no effective way to relieve OA-induced pain. Despite the major negative impact that severe pain in chronic OA has on quality of life and health care management, we only poorly understand origins of pain in OA, the molecular mechanisms driving the pathology, and the way to effectively cure OA. Many cases eventually require joint replacement with a prosthesis which is costly, and the limited functional life of prostheses (~10 y) can make a second replacement necessary. These factors increase both the overall cost of treatment and the risk for associated morbidity. Significantly, surgical procedures to address the condition typically do not result in a pain-free cure. Our central hypothesis is that activation of Flt1 (vascular endothelial growth factor receptor-1) is the major driver of joint pain transmission by plasticity of peripheral (sensory neurons) and central glial activation; Flk1 (vascular endothelial growth factor receptor-2) is primarily responsible for cartilage degeneration during the OA progression, thus, simultaneous inhibition of Flt1 and Flk1 by pazopanib, an FDA-approved small molecule anti-cancer drug, will act as an ideal OA disease-modifying drug (OADMD) with immediate reduction of joint pain and gradually cartilage regeneration. The findings of our proposed research will take the field of OA research a giant step forward: in the short term, by increasing our mechanistic understanding of the causes and progression of OA, and by developing a novel strategy for treating OA and joint pain effectively and safely in our pre-clinical OA animal model; and, in the longer term, by providing a rationale for clinical trials to test pazopanib to treat OA patients.