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，目前尚无治疗方法 通过 OA 逆转关节恶化。目前的护理标准包括疼痛管理和 最终，针对晚期骨关节炎的关节置换手术。最近治疗 OA 疼痛的策略重点是 抑制神经生长因子 (NGF)，神经生长因子是 OA 伤害性疼痛的主要介质。神经生长因子抗体 有效减轻骨关节炎疼痛；然而，一小部分接受抗 NGF 抗体治疗的患者 膝关节和髋关节出现快速进展/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。此次合作的长期目标是了解 RPOA 的病理生理学并确定预防策略。 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）存在于感觉神经元中，可以增强感觉神经元的生长和 外周轴突的分支：这两种效应都可能导致 OA 疼痛，并通过以下方式强调了这一机制： 抗 NGF 抗体可实现镇痛作用。除了它们在检测疼痛方面的作用之外 顺向神经递质释放；然而，感觉神经元也会影响周围组织 通过神经递质逆向释放到局部微环境中。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 血管扩张。基于 CGRP 的这种新作用，我们假设局部释放 软骨下骨中的 CGRP 是维持血流和骨形成所必需的 OA 关节，以及抗 NGF 诱导的 CGRP 信号传导丧失，有助于加速 通过损害软骨下骨完整性而导致 OA 关节退化。 RPOA 的风险是 高剂量抗 NGF 抗体、同时使用 NSAID 和低骨矿物质会增加 低雌激素水平引起的密度，所有因素都会减少 CGRP 的神经元释放，支持 局部 CGRP 可以预防进行性 OA。在目标 1 中，我们将确定 在不存在和存在 NSAID 的情况下，抗 NGF 治疗对老年人膝关节 OA 严重程度的影响 雄性和雌性小鼠。我们将检验以下假设：抗 NGF 和 NSAID 治疗可减少 内侧半月板 (DMM) 手术不稳定的动物软骨下骨中的 CGRP， 导致软骨下骨量和小梁结构改变，这与膝关节有关 OA 严重程度。如果成功，目标 1 将生成第一个 RPOA 动物模型。在目标 2 中，我们将确定 抗 CGRP 治疗是否会重现抗 NGF 治疗引起的 OA 关节退化 使用 DMM 测试老年雌性小鼠，以检验抑制 CGRP 信号传导会损害 OA动物模型中软骨下骨的完整性。这些研究将有助于确定 感觉神经元传出神经递质的释放，尤其是 CGRP，以调节神经递质的完整性 OA 中的软骨下骨。