Molecular Pathways of Pain Generation in Osteoarthritis

描述（由申请方提供）：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，是美国老年人群活动能力受损的主要原因之一。我们缺乏对慢性疼痛机制的了解，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。尽管它对生活质量和医疗保健管理有重大影响，但我们对人类OA疼痛机制的理解仍然非常差。该提案的长期目标是确定OA疼痛的起源和机制，从而能够识别新的靶点，并开发OA疼痛的新疗法和生物标志物。令人信服的激励数据，沿着新型转基因小鼠，为这一高度欠研究的领域的立即研究和快速发展创造了独特的机会。这些研究的目标有三个：1）使用经验证的鼠OA模型，内侧半月板（DMM）的不稳定，以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）中的并发细胞和结构变化。目的是使用评估机械性异常性疼痛、自发性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。将疼痛测量与所有关节组织（软骨、骨、滑膜和半月板）中的病理变化以及关节和背根神经节中传入神经突的数量和位置的伴随变化进行详细关联; 2）确定抑制ADAMTS-5对与DMM模型中的结构关节和神经元变化相关的检测到的疼痛的影响。抑制将在体内实现，a）通过使用Adamts-5缺失小鼠，和B）通过用强效和选择性抑制剂药理学抑制ADAMTS-5。在DMM模型中，缺乏活性ADAMTS-5可防止OA进展。ADAMTS-5抑制剂正在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。这些研究应该使我们能够确定这些抑制剂是否也会影响疼痛，以及在疾病发作后多久，与OA结构变化相关的疼痛是可逆的，或者在什么阶段疼痛变得不可逆。研究结果有望对人类OA疼痛管理具有重要意义; 3）通过对伤害性通路、胶质细胞活化和透明质酸片段的分子标志物的时间分析，在DMM模型中剖析参与OA相关疼痛的发作和慢性化的分子通路。具体而言，时间的作用，神经生长因子介导的和MCP-1介导的伤害感受器途径将进行探讨。这些动物研究中涉及的基因将为大型人类OA队列中的遗传连锁分析提供基础，这些队列具有已知的疼痛和残疾指标，如WOMAC评分。 公共卫生相关性：骨关节炎伴随的疼痛是一个主要的未满足的医疗需求。了解导致骨关节炎慢性疼痛的细胞和分子机制将对缓解疼痛的治疗产生重大影响，并可能应用于其他肌肉骨骼疼痛。

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.