The Role of Calcitonin Gene-Related Peptide in rapidly progressive osteoarthritis induced by anti-nerve growth factor

骨关节炎是疼痛和残疾的主要原因，目前还没有治疗方法 与骨性关节炎逆转关节恶化。目前的护理标准包括疼痛管理和 最终，关节置换手术治疗晚期骨性关节炎。最近治疗骨性关节炎疼痛的策略主要集中在 抑制神经生长因子(NGF)，这是骨性关节炎伤害性疼痛的主要媒介。NGF抗体 有效地减轻了骨性关节炎的疼痛；然而，接受抗NGF抗体治疗的患者比例很小 患上膝关节和髋关节的快速进行性/破坏性骨关节炎(RPOA)，需要关节置换术； 然而，RPOA的确切病因尚不清楚。此次合作的长期目标是了解 RPOA的病理生理学，并找出预防策略。NGF上调离子通道， 炎症介质受体和信号神经肽，包括P物质(SP)和 降钙素基因相关肽(CGRP)在感觉神经元中的表达，并能促进神经元的生长和发育 外周轴突的分支：这两种效应都可能导致骨性关节炎疼痛，并通过以下方式强调其机制 哪些抗NGF抗体可以实现抗伤害作用。除了它们在检测疼痛方面的作用之外 顺序性神经递质释放；然而，感觉神经元也可以影响周围组织 通过神经递质的逆行释放进入局部微环境。在关节中，神经元 释放CGRP刺激骨形成，减少骨吸收，刺激血管生成和 血管扩张。基于CGRP的这一新作用，我们假设局部释放 软骨下骨中降钙素基因相关肽的表达是维持血液循环和骨形成所必需的 抗NGF诱导骨关节炎关节和CGRP信号丢失促进加速 关节退行性变损害了软骨下骨的完整性。RPOA的风险是 高剂量的抗NGF抗体，伴随非甾体抗炎药的使用和低骨矿物质的使用而增加 低雌激素水平引起的密度，所有减少神经细胞释放CGRP的因素，支持 认为局部CGRP对进行性骨性关节炎有保护作用的观点。在目标1中，我们将确定 非甾体抗炎药和非甾体抗炎药联合抗NGF治疗对老年膝关节骨性关节炎严重程度的影响 雄性和雌性小鼠。我们将检验抗NGF和非甾体抗炎药治疗可以减少 内侧半月板手术失稳动物软骨下骨中CGRP的表达 导致软骨下骨量和骨小梁结构改变，这与膝关节有关 骨性关节炎的严重性。如果成功，AIM 1将产生第一个RPOA动物模型。在目标2中，我们将确定 抗CGRP治疗是否会重演NGF治疗所致的骨关节炎关节退变 用DMM衰老雌性小鼠来验证CGRP信号的抑制会损害 骨关节炎动物模型中软骨下骨的完整性。这些研究将有助于确定 感觉神经元传出释放神经递质，尤其是降钙素基因相关肽，调节 骨性关节炎的软骨下骨。

Osteoarthritis (OA) is a major cause of pain and disability and there are currently no treatments that reverse the joint deterioration with OA. The current standard of care involves pain management and ultimately, joint replacement surgery for advanced OA. A recent strategy to treat OA pain is focused on inhibition of nerve growth factor (NGF), a major mediator of nociceptive pain in OA. NGF antibodies effectively reduce OA pain; however, a small percentage of patients treated with anti-NGF antibodies develop a rapidly progressive/ destructive OA (RPOA) of the knee and hip that requires joint replacement; however, the precise etiology of RPOA is unclear. The long term goal of this collaboration is to understand the pathophysiology of RPOA and identify strategies to prevent it. NGF upregulates ion channels, receptors for inflammatory mediators, and signaling neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP) in sensory neurons and can enhance the outgrowth and branching of peripheral axons: both effects likely contribute to OA pain and underscore the mechanism by which anti-NGF antibodies achieve antinociception. In addition to their role in detecting pain via orthodromic neurotransmitter release; however, sensory neurons also can affect peripheral tissues through the antidromic release of neurotransmitters into the local microenvironment. In the joint, neuronal release of CGRP stimulates bone formation, reduces bone resorption and stimulates angiogenesis and vasodilatation of blood vessels. Based on this novel role of CGRP, we hypothesize that local release of CGRP in the subchondral bone is required for maintenance of bloodflow and bone formation in the OA joint, and that loss of CGRP signaling, induced by anti-NGF, facilitates accelerated degeneration of the OA joint by compromising subchondral bone integrity. The risk for RPOA is increased by high doses of anti-NGF antibodies, concomitant NSAID use and low bone mineral density caused by low estrogen levels, all factors that diminish the neuronal release of CGRP, supporting the notion that local CGRP could be protective against progressive OA. In Aim 1, we will determine the effects of anti-NGF therapy, in the absence and presence of NSAIDs, on the severity of knee OA in aged male and female mice. We will test the hypothesis that treatment with anti-NGF and NSAIDs reduce CGRP in subchondral bone in animals with surgical destabilization of the medial meniscus (DMM), resulting in altered subchondral bone mass and trabecular structure, and that this is associated with knee OA severity. If successful, Aim 1 will generate the first animal model of RPOA. In Aim 2, we will determine if anti-CGRP treatment will recapitulate the degeneration of the OA joint induced by anti-NGF therapy in aged female mice with DMM to test the hypothesis that inhibition of CGRP signaling compromises the integrity of subchondral bone in the animal model of OA. These studies will help to identify a role for efferent release of neurotransmitters from sensory neurons, especially CGRP, to regulate the integrity of subchondral bone in OA.