Molecular Pathways of Pain Generation in Osteoarthritis

描述（由申请人提供）：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，是美国老年人活动能力受损的主要原因之一。我们对慢性疼痛的机制缺乏了解，特别是与OA相关的慢性疼痛，这是目前可用治疗方案普遍无效的原因。缓解严重OA疼痛仍然是一个未满足的医疗需求，也是寻求手术干预的主要原因。尽管骨关节炎对生活质量和医疗保健管理有重大影响，但我们对骨关节炎疼痛机制的理解仍然很差。本提案的长期目标是明确OA疼痛的起源和机制，从而确定OA疼痛的新靶点，开发新的治疗方法和生物标志物。令人信服的激励数据，以及新型转基因小鼠，为这个高度研究不足的领域的即时研究和快速发展创造了一个独特的机会。这些研究的目标有三个方面：1)使用经过验证的小鼠OA模型，内侧半月板不稳定（DMM），定量测量疼痛并确定关节组织及其感觉神经支配（外周成分和背根神经节）的细胞和结构变化。目的是利用评估机械异常性疼痛、自发疼痛行为和步态的技术，对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）的病理变化以及伴随的关节和背根神经节传入神经的数量和位置的变化详细相关；2)确定抑制ADAMTS-5对DMM模型关节结构和神经元变化相关疼痛的影响。体内抑制将通过a)使用Adamts5缺失小鼠和b)使用强效和选择性抑制剂对ADAMTS-5进行药理学抑制来实现。在DMM模型中，缺乏活性ADAMTS-5可以防止OA进展。ADAMTS-5抑制剂正被开发为改善疾病的OA药物，但对其影响疼痛的潜力还没有明确的认识。这些研究应该允许我们确定这些抑制剂是否也会影响疼痛，以及疾病发作后多久与OA结构改变相关的疼痛是可逆的，或者在什么阶段疼痛是不可逆转的。这里的研究结果有望对人类OA的疼痛管理产生重要影响；3)通过痛觉通路、神经胶质活化和透明质质片段的分子标记物的时间分析，解剖DMM模型中参与oa相关疼痛发病和慢性的分子通路。具体来说，我们将探讨ngf介导和mcp -1介导的伤害感受器通路在时间上的作用。这些动物研究中涉及的基因将为具有已知疼痛和残疾指标（如WOMAC评分）的大型人类OA队列的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. PUBLIC HEALTH RELEVANCE: The pain that accompanies osteoarthritis represents a major unmet medical need. Understanding the cellular and molecular mechanisms that lead to chronic pain in osteoarthritis will have a major impact on treatments for pain relief, with potential applications to other musculoskeletal pain.