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

降钙素基因相关肽在抗神经生长因子诱导的快速进展性骨关节炎中的作用

• 批准号: 10625381
• 负责人: JILL C FEHRENBACHER
• 金额: $ 19.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625381
• 关键词: Acceleration; Adverse effects; Affect; Afferent Neurons; Animal Model; Animals; Antibodies; Architecture; Arthralgia; Axon; Binding; Blood Vessels; Blood flow; Bone Density; Bone Formation Stimulation; Bone Resorption; Bone structure; Calcitonin Gene-Related Peptide; Cartilage; Clinical; Collaborations; Degenerative polyarthritis; Deterioration; Dinoprostone; Dose; Elderly; Estrogens; Etiology; Female; Functional disorder; Future; Goals; Hip Osteoarthritis; Homeostasis; Inflammation; Inflammation Mediators; Ion Channel; Joints; Knee Osteoarthritis; Knee joint; Maintenance; Medial meniscus structure; Mediating; Mediator; Medical History; Meniscus structure of joint; Mus; Nerve Fibers; Nerve Growth Factors; Neurons; Neuropeptides; Neurotransmitters; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Osteogenesis; Pain; Pain management; Pathology; Patient Self-Report; Patients; Peptide Signal Sequences; Peripheral; Phosphotransferases; Play; Post-Translational Protein Processing; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Replacement Arthroplasty; Risk; Role; Severities; Signal Transduction; Structure; Study Subject; Substance P; Synovial Membrane; Synovitis; Testing; Therapeutic Intervention; Time; Tissues; Treatment Factor; Tropomyosin; Unipolar Neuron; Up-Regulation; Vasodilation; afferent nerve; aged; angiogenesis; antinociception; arthropathies; bone; bone mass; cartilage degradation; clinical development; disability; healing; joint loading; male; mechanical load; neurotransmitter release; novel; osteoarthritis pain; pain perception; pain reduction; phase III trial; prevent; receptor; response; skeletal; standard of care; subchondral bone

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.

骨关节炎（OA）是疼痛和残疾的主要原因，目前没有治疗方法， 逆转OA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OA。最近治疗OA疼痛的策略集中在 抑制神经生长因子（NGF），OA中伤害性疼痛的主要介质。NGF抗体 有效地减少OA疼痛;然而，一小部分用抗NGF抗体治疗的患者 发生膝关节和髋关节的快速进行性/破坏性OA（RPOA），需要进行关节置换; 然而，RPOA的确切病因尚不清楚。这项合作的长期目标是了解 RPOA的病理生理学，并确定策略，以防止它。神经生长因子上调离子通道， 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）在感觉神经元中的作用，并能促进生长， 外周轴突的分支：这两种效应都可能导致OA疼痛，并强调了 其中抗NGF抗体实现抗伤害感受。除了它们在检测疼痛中的作用外， 顺向神经递质释放;然而，感觉神经元也可以影响外周组织 通过逆向释放神经递质进入局部微环境。在关节中，神经元 CGRP的释放刺激骨形成、减少骨吸收并刺激血管生成， 血管的扩张。基于CGRP的这种新作用，我们假设局部释放 CGRP在软骨下骨中的含量是维持血液流动和骨形成所必需的， OA关节，以及抗NGF诱导CGRP信号传导的丧失，促进了加速的 通过损害软骨下骨完整性导致OA关节退化。RPOA的风险是 高剂量抗NGF抗体、伴随NSAID使用和低骨矿物质增加 密度引起的低雌激素水平，所有的因素，减少神经元释放的CGRP，支持 局部CGRP可能对进行性OA具有保护作用。在目标1中，我们将确定 抗神经生长因子治疗对老年人膝关节骨性关节炎严重程度的影响 雄性和雌性小鼠。我们将检验用抗神经生长因子和非甾体抗炎药治疗可以减少 内侧半月板（DMM）手术失稳动物软骨下骨中的CGRP， 导致软骨下骨质量和骨小梁结构改变，这与膝关节炎相关。 OA严重程度。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治疗是否会重演抗NGF治疗诱导的OA关节退行性变， 老年雌性小鼠与DMM测试的假设，CGRP信号的抑制损害 软骨下骨的完整性。这些研究将有助于确定 从感觉神经元传出神经递质的释放，尤其是CGRP，以调节 OA的软骨下骨。