Neuronal Modulation of Focal Bone Homeostasis

描述(申请人提供)：为了探索肌肉和骨骼之间相互依赖的特定信号通路，我们开发了一种新的在体小鼠一过性肌肉麻痹模型，该模型在肌肉注射A型肉毒毒素(BTxA)后抑制运动和感觉信号。尽管有轻微和短暂的步态缺陷，但我们已经表明，短暂性肌肉瘫痪后的骨小梁丢失迅速而严重，并以RANKL介导的破骨细胞吸收为主。我们对小鼠后肢本体感觉缺陷的初步数据使我们假设骨小梁的动态平衡受神经肌肉本体感觉的调节。在这个项目中，我们将通过四个密切相关的子假设来推进这篇论文，每个子假设都有相应的特定目标。前三个S.目标试图证明，虽然机械刺激明显影响骨小梁的动态平衡，但肌肉本体感觉在调节局部骨小梁形态方面起着先前未被认识的但基本的作用。在最后一篇论文中，我们将试图阐明，神经元介导的炎症反应先于并介导了短暂性肌肉麻痹所引起的严重的破骨细胞吸收。如果这些数据支持我们的假设，我们相信我们的结果有可能改变目前干预或预防各种肌肉骨骼病理中骨丢失的方法。 与公共健康相关：这个项目试图阐明一种基本的，但尚未被认识的神经元途径，通过它实现和维持正常的骨小梁稳态。从临床角度来看，我们认为，了解感觉本体感觉在调节局部骨小梁稳态中所起的作用，将直接使对急性(如脊髓损伤、全身停用)和慢性(如与衰老有关)骨丢失病理的新干预措施成为可能。

DESCRIPTION (provided by applicant): In part to explore the specific signaling pathways that underlie the co-dependency between muscle and bone, we have developed a novel in vivo murine model of transient muscle paralysis that inhibits both motor and sensory signaling following intramuscular injections of botulinum toxin A (BTxA). Despite a mild and transient gait deficit, we have shown that the loss of trabecular bone following transient muscle paralysis is rapid and profound and dominated by RANKL mediated osteoclastic resorption. Our preliminary data with a mouse hindlimb specific defect in proprioception has led us to hypothesize that trabecular bone homeostasis is modulated by neuromuscular proprioception. In this project we will pursue this thesis through four closely related sub-hypotheses each with a corresponding Specific Aim. The first three S. Aims seek to demonstrate that while mechanical stimuli clearly influence trabecular bone homeostasis, muscle proprioception plays a previously unrecognized, but fundamental role in modulating local trabecular bone morphology. In the final S. Aim we will attempt to clarify that a neuronally mediated inflammatory response precedes and mediates the profound osteoclastic resorption acutely induced by transient muscle paralysis. If these data support our hypothesis, we believe that our results hold potential to alter current approaches to intervene or prevent bone loss in a variety of musculoskeletal pathologies. PUBLIC HEALTH RELEVANCE: This project seeks to elucidate a fundamental, but as yet unrecognized neuronal pathway by which normal trabecular bone homeostasis is achieved and maintained. From a clinical perspective, we believe that understanding the role that sensory proprioception plays in modulating local trabecular bone homeostasis will directly enable novel interventions into both acute (e.g., spinal cord injury, general disuse) and chronic (e.g., associated with aging) bone loss pathologies.