Neuronal Modulation of Focal Bone Homeostasis

描述（由申请人提供）：部分为了探索肌肉和骨骼之间相互依赖性的特定信号传导途径，我们开发了一种新型的短暂性肌肉麻痹的体内鼠模型，其在肌肉内注射肉毒杆菌毒素A（BTxA）后抑制运动和感觉信号传导。尽管存在轻度和短暂的步态缺陷，但我们已经证明，短暂性肌肉麻痹后骨小梁的丢失是快速和严重的，并以RANKL介导的骨吸收为主。我们的初步数据与小鼠后肢特定缺陷的本体感觉，使我们假设，骨小梁稳态是由神经肌肉本体感觉调制。在这个项目中，我们将通过四个密切相关的子假设，每个子假设都有一个相应的具体目标来实现这一点。前三个S。目的是试图证明，虽然机械刺激明显影响骨小梁稳态，肌肉本体感受发挥了以前未被认识到的，但在调制局部骨小梁形态的基本作用。在最后的S.目的：我们将试图阐明神经介导的炎症反应先于并介导短暂性肌肉麻痹急性诱导的严重骨吸收。如果这些数据支持我们的假设，我们相信我们的研究结果有可能改变目前干预或预防各种肌肉骨骼病变中骨丢失的方法。 公共卫生相关性：本项目旨在阐明一个基本的，但尚未认识到的神经元通路，通过该通路实现和维持正常的骨小梁稳态。从临床的角度来看，我们相信，了解感觉本体感受在调节局部骨小梁稳态中的作用将直接使新的干预措施成为可能，脊髓损伤，一般废用）和慢性（例如，与老化相关）骨丢失病理学。

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.