Mechanisms of hypovitaminosis D-induced muscle sensitivity

描述（由申请人提供）：肌肉骨骼疼痛影响大约一半的美国成年人口，导致生产力的巨大损失。维生素D缺乏症也非常普遍。临床研究表明，易患维生素D缺乏症的人群，包括老年人和肥胖者，更有可能经历肌肉疼痛。此外，据报道，维生素D补充可有效缓解肌肉疼痛。然而，维生素D缺乏引起疼痛的生物学基础尚不清楚。我们发现背根神经节感觉神经元表达维生素D受体，并开发了一种显示深层肌肉敏感性的维生素D缺乏大鼠模型。这些大鼠的腓肠肌显示神经支配指数增加，与许多外周疼痛综合征中感觉轴突密度增加一致。本研究的目的是探讨维生素D缺乏、感觉神经支配和肌肉疼痛之间的关系。我们假设维生素D缺乏导致骨骼肌感觉伤害感受器轴突发芽。在第一个具体的目标，我们将表征外周靶神经支配的神经支配密度，神经元表型的变化，并在正常或缺乏维生素D的大鼠激活脊髓通路的能力。在第二个目标中，我们将确定生理和低生理浓度的维生素D对轴突生长的直接影响，从分离的成人背根神经节神经元培养。我们还将通过对正常或维生素D缺乏大鼠的神经节和骨骼肌进行外植体培养，并评估肌肉调节神经突生长的能力，来研究靶组织的作用。这些研究代表了维生素D缺乏引起的肌肉疼痛的生物学基础的首次系统探索。他们也是第一个研究维生素D在成熟轴突生长中的作用。这项探索性研究的结果将为使用大鼠模型的其他机制研究以及记录维生素D在预防和逆转疼痛综合征中的效用的临床研究提供基础。 公共卫生相关性：肌肉骨骼疼痛和维生素D缺乏在美国人群中很普遍，临床研究表明存在因果关系。然而，维生素D缺乏导致肌肉疼痛的生物学基础尚不清楚。我们提出了关于维生素D缺乏导致肌肉疼痛的细胞机制的第一个系统研究。这些研究将为采用维生素D补充剂作为预防或治疗方法提供基于证据的理由，以解决每年花费美国经济超过400亿美元的问题。

DESCRIPTION (provided by applicant): Musculo-skeletal pain affects roughly half of the adult US population, resulting in enormous loss of productivity. Vitamin D deficiency is also extremely prevalent. Clinical studies suggest that populations prone to vitamin D deficiency, including the elderly and obese, are much more likely to experience muscle pain. Further, vitamin D repletion is reported to be effective in ameliorating muscle pain. However, the biological basis for hypovitaminosis D-induced pain is unclear. We've found that dorsal root ganglion sensory neurons express vitamin D receptors, and developed a rat model of vitamin D deficiency showing deep muscle sensitivity. Gastrocnemius muscle from these rats show increased indices of innervation, consistent with increased sensory axon density in a number of peripheral pain syndromes. The objective of this proposal is to explore the relation among vitamin D deficiency, sensory innervation and muscle pain. We hypothesize that vitamin D deficiency leads to sprouting of sensory nociceptor axons in skeletal muscle. In the first specific aim, we will characterize peripheral target innervation with regard to changes in innervation density, neuronal phenotype, and ability to activate spinal pathways in rats with normal or deficient vitamin D. In the second aim, we will determine direct effects of physiological and hypophysiological concentrations vitamin D on axon outgrowth from dissociated adult dorsal root ganglion neuronal cultures. We will also examine the role of target tissue by conducting explant cultures of ganglion and skeletal muscle from normal or vitamin D- deficient rats and assessing the muscle's ability to modulate neurite outgrowth. These studies represent the first systematic exploration of the biological basis of hypovitaminosis D-induced muscle pain. They are also the first to investigate a role of vitamin D in mature axonal outgrowth. Results from this exploratory study will provide a basis for additional mechanistic investigations using the rat model, and for clinical studies documenting the utility of vitamin D in preventing and reversing pain syndromes. PUBLIC HEALTH RELEVANCE: Both musculo-skeletal pain and vitamin D deficiency are widespread within the US population, and clinical studies suggest that a causal relationship exists. However, the biological basis by which vitamin D deficiency leads to muscle pain is unclear. We propose the first systematic investigation concerning cellular mechanisms by which vitamin D deficiency leads to muscle pain. These studies will provide an evidence-based rationale for employing vitamin D supplementation as a preventative or therapeutic approach to a problem that costs the US economy in excess of $40 billion per year.