Molecular Pathways of Pain Generation in Osteoarthritis

描述(申请人提供)：疼痛是骨关节炎(OA)的主要症状，导致功能受损和生活质量下降，也是美国老年人口行动不便的主要原因之一。我们普遍缺乏对慢性疼痛，特别是与骨性关节炎相关的慢性疼痛机制的了解，这是目前可用的治疗方案普遍无效的原因。缓解严重的骨性关节炎疼痛仍然是一个未得到满足的医疗需求，也是寻求手术干预的一个主要原因。尽管它对生活质量和医疗保健管理有重大影响，但我们对人类骨性关节炎疼痛机制的了解仍然很少。这项建议的长期目标是确定骨性关节炎疼痛的起源和机制，从而能够识别新的靶点，并为骨性关节炎疼痛开发新的治疗方法和生物标志物。令人信服的激励数据，以及新的转基因小鼠，为在这个高度未被研究的领域立即进行研究和迅速取得进展创造了一个独特的机会。这些研究的目标有三个：1)使用一个经过验证的小鼠OA模型，内侧半月板失稳(DMM)，以定量测量疼痛，并确定关节组织及其感觉神经(外周成分和背根神经节)同时发生的细胞和结构变化。其目标是使用评估机械性超感痛觉、自发性疼痛行为和步态的技术，对疾病16周病程中的疼痛进行定性和定量评估。疼痛测量将与所有关节组织(软骨、骨、滑膜和半月板)的病理变化以及关节和背根神经节中传入神经突起的数量和位置的伴随变化进行详细的相关性研究；2)确定抑制ADAMTS-5对DMM模型中与结构关节和神经元变化相关的疼痛的影响。在体内，a)通过使用Adamts5基因缺失的小鼠，b)通过用有效和选择性的抑制剂药理抑制ADAMTS-5，将实现抑制。在DMM模型中，缺乏活性的ADAMTS-5可以防止OA的进展。ADAMTS-5抑制剂正在被开发为治疗骨性关节炎的疾病药物，但对其影响疼痛的潜力没有明确的了解。这些研究应该使我们能够确定这些抑制剂是否也会影响疼痛，以及与骨性关节炎结构变化相关的疼痛在发病后多长时间是可逆的，或者在什么阶段疼痛已经不可逆转。3)通过对伤害性通路、神经胶质细胞激活和透明质连蛋白片段分子标志物的时间分析，剖析DMM模型中参与骨性关节炎相关疼痛发生和慢性的分子通路。具体地说，将探索NGF和MCP-1介导的伤害性感受器通路的时间作用。这些动物研究中涉及的基因将为在具有已知疼痛和残疾指标(如WOMAC评分)的大型人类骨性关节炎队列中进行遗传连锁分析提供基础。

DESCRIPTION (provided by applicant): Pain is the major symptom in osteoarthritis (OA), contributing to impaired function and loss of quality of life, and one of the leading causes of impaired mobility in the elderly population in the US. Our lack of understanding the mechanisms underlying chronic pain in general, and chronic pain associated with OA in particular, accounts for the general ineffectiveness of currently available treatment options. Relief from severe OA pain remains an unmet medical need and a major reason for seeking surgical intervention. In spite of its major impact on quality of life and health care management, our understanding of the mechanisms of pain in human OA remains very poor. The long-term goal of this proposal is to define origins and mechanisms of pain in OA, thus enabling identification of new targets, and development of new therapies and biomarkers for OA pain. Compelling motivating data, along with novel genetically modified mice, have created a unique opportunity for immediate studies and rapid advances in this highly understudied area. The goal of these studies is three-fold: 1) Use a validated murine OA model, destabilization of the medial meniscus (DMM), to quantitatively measure pain and determine concurrent cellular and structural alterations in joint tissues and their sensory innervation (peripheral component and dorsal root ganglia). The goal is to make a qualitative and quantitative assessment of pain in the 16-week course of the disease using techniques that evaluate mechanical allodynia, spontaneous pain behavior and gait. A detailed correlation of pain measures will be made with pathological changes in all joint tissues (cartilage, bone, synovium, and meniscus) and with concomitant changes in the number and location of afferent neurites in the joint and dorsal root ganglia; 2) Determine the effect of inhibiting ADAMTS-5 on pain detected in association with structural joint and neuronal changes in the DMM model. Inhibition will be achieved in vivo a) by using Adamts5 null mice and b) by pharmacological inhibition of ADAMTS-5 with potent and selective inhibitors. The absence of active ADAMTS-5 protects against OA progression in the DMM model. ADAMTS-5 inhibitors are being developed as disease-modifying OA drugs, without clear understanding of their potential to affect pain. These studies should allow us to determine whether these inhibitors will also affect pain, and how long after onset of disease the pain associated with OA structural changes is reversible or at what stage the pain has become irreversible. Findings here are expected to have important implications for pain management in human OA; 3) Dissect molecular pathways participating in onset and chronicity of OA-related pain in the DMM model, through temporal analysis of molecular markers of nociceptive pathways, glial activation, and hyalectan fragments. Specifically, the temporal role of the NGF-mediated and the MCP-1-mediated nociceptor pathway will be explored. Genes implicated in these animal studies will provide the basis for genetic linkage analysis in large human OA cohorts with known pain and disability measures such as the WOMAC score.