Bone Marrow Inflammation and Bone Resorption

骨髓炎症和骨吸收

• 批准号: 10295620
• 负责人: TED S. GROSS
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295620
• 关键词: Acute; Antihistamines; Attenuated; Bone Marrow; Bone Resorption; Botulinum Toxin Type A; Calcitonin Gene-Related Peptide; Clinical; Connective Tissue; Critical Pathways; Data; Functional disorder; Gene Expression; Genes; Goals; Histamine; Histamine Antagonists; Histamine H2 Antagonists; Histamine Receptor; Histamine Release; Homeostasis; Impairment; Individual; Inflammation; Inflammatory; Injury; Link; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Contraction; Muscle function; Nerve; Neurogenic Inflammation; Neuropeptides; Outcome; Paralysed; Pathway interactions; Pharmaceutical Preparations; Physiology; Proto-Oncogene Protein c-kit; Series; Signal Pathway; Signal Transduction; Skeleton; Substance P; TNFSF11 gene; Therapeutic; afferent nerve; bone; bone loss; cortical bone; experience; mast cell; mechanical load; mouse model; neuromuscular; neuromuscular function; novel strategies; osteoclastogenesis; prevent; response; skeletal; substantia spongiosa; tibia; translational approach

PROJECT SUMMARY/ABSTRACT Data from our mouse model of Botulinum Toxin A (BTxA) induced muscle paralysis has revealed that neuromuscular function, outside the axis of mechanical loading deficits, is a critical modulator of bone homeostasis. Consistent with this thesis, we have observed that transient muscle paralysis triggers acute inflammatory signaling within bone marrow that precedes the onset of focal RANKL-mediated osteoclastogenesis, which is responsible for the profound cortical and trabecular bone resorption observed in the model. However, the intercellular signaling that initiates acute bone marrow inflammation and subsequent bone resorption has not been elucidated and therefore presents a barrier to identifying translational strategies that would decouple neuromuscular dysfunction from bone loss. One potential initiator of this rapid response is neurogenic inflammation, which is triggered by neuropeptide release from sensory nerves and is amplified by mast cell mediated histamine release. We therefore pursued a series of preliminary studies to assess activation of this pathway following muscle paralysis and found that: 1) Substance P, a classic initiator of neurogenic inflammation, was upregulated in tibia bone marrow within 1 d of calf paralysis, 2) genes associated with connective tissue mast cell activation were acutely elevated following muscle paralysis, and 3) muscle paralysis induced bone resorption was significantly diminished in mast cell deficient KitW-sh/W-sh mice. We therefore hypothesize that: Bone resorption following muscle paralysis is initiated by neuropeptide signaling and is amplified by mast cell dependent histamine release. We will pursue this thesis via four complementary Specific Aims (SA), each with a corresponding sub-hypothesis. First, we anticipate that neuropeptides within bone marrow will be elevated by BTxA induced muscle paralysis prior to evidence of mast cell activation or bone resorption (SA#1). SA#2 will then demonstrate that successful antagonism of these neuropeptides will be required to inhibit mast cell activation and bone resorption induced by muscle paralysis. In SA#3, we will leverage a cKit independent, connective tissue mast cell deficient mouse to demonstrate that mast cell mediated histamine signaling is responsible for the profound osteoclastogenesis induced by muscle paralysis. SA#4 will then provide proof of concept that treatment with histamine receptor antagonists will significantly attenuate bone resorption caused by muscle paralysis. Each aspect of the proposed signaling pathway (neurogenic inflammation, neuropeptide signaling, mast cell activation, paralysis induced bone resorption) has been explored in other contexts but has not been integrated into a cellular signaling cascade that integrates muscle, nerve, and bone physiology. Importantly, if our thesis is supported, the broad clinical experience with histamine antagonists will enable repurposing of approved drugs toward the goal of ameliorating acute bone resorption precipitated by paralysis or other neuromuscular impairments.

项目总结/摘要 来自我们的肉毒杆菌毒素A（BTxA）诱导的肌肉麻痹的小鼠模型的数据显示， 神经肌肉功能，轴外的机械负荷赤字，是一个关键的调制器骨 体内平衡与这一论点一致，我们观察到短暂的肌肉麻痹触发急性 在局灶性RANKL介导的骨髓炎性信号传导开始之前， 破骨细胞生成，这是负责观察到的深度皮质和小梁骨吸收， 该模型然而，启动急性骨髓炎症和随后的细胞间信号传导， 骨吸收尚未阐明，因此对确定翻译策略提出了障碍 这将使神经肌肉功能障碍与骨质流失脱钩。这种快速反应的一个潜在发起者是 神经源性炎症，其由感觉神经释放的神经肽触发，并通过 肥大细胞介导的组胺释放。因此，我们进行了一系列初步研究， 在肌肉麻痹后激活这一通路，发现：1）P物质，一种经典的 神经源性炎症，在小腿瘫痪1天内在胫骨骨髓中上调，2）基因 与结缔组织肥大细胞活化相关的肌肉麻痹后急性升高，和3） 在肥大细胞缺陷的KitW-sh/W-sh小鼠中，肌肉麻痹诱导的骨吸收显著减少。 因此，我们假设：肌肉麻痹后的骨吸收是由神经肽启动的 信号传导并通过肥大细胞依赖性组胺释放而放大。我们将通过四个方面来探讨这一论题。 互补的具体目标（SA），每个都有相应的子假设。首先，我们预计， 骨髓内的神经肽将通过BTxA诱导的肌肉麻痹而升高， 肥大细胞活化或骨吸收（SA#1）。然后，SA#2将证明成功拮抗 需要这些神经肽来抑制肥大细胞活化和肌肉诱导的骨吸收 瘫痪在SA#3中，我们将利用不依赖cKit的结缔组织肥大细胞缺陷小鼠， 表明肥大细胞介导的组胺信号传导是造成严重破骨细胞生成的原因， 由肌肉麻痹引起的SA#4将提供组胺受体治疗的概念证明， 拮抗剂将显著减弱由肌肉麻痹引起的骨吸收。的每个方面 提出的信号传导途径（神经源性炎症、神经肽信号传导、肥大细胞活化、麻痹 诱导的骨吸收）已经在其他背景下进行了探索，但尚未整合到细胞内。 整合肌肉、神经和骨骼生理学的信号级联。重要的是，如果我们的论点得到支持， 组胺拮抗剂的广泛临床经验将使批准的药物能够重新用于 目的是改善由瘫痪或其他神经肌肉损伤引起的急性骨吸收。