Mechanisms of hypovitaminosis D-induced muscle sensitivity

描述(申请人提供)：肌肉骨骼疼痛影响大约一半的美国成年人口，导致巨大的生产力损失。维生素D缺乏症也非常普遍。临床研究表明，容易缺乏维生素D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，补充维生素D在缓解肌肉疼痛方面有效。然而，维生素D缺乏症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，并建立了维生素D缺乏的大鼠模型，显示出深度的肌肉敏感性。这些大鼠的腓肠肌表现出神经支配指数的增加，这与许多外周疼痛综合征中感觉轴突密度的增加一致。本建议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缺乏会导致骨骼肌中感觉伤害感受器轴突的萌发。在第一个目标中，我们将从神经密度、神经元表型和激活脊髓通路的能力的变化来表征周围靶神经的变化。在第二个目标中，我们将确定生理和生理浓度的维生素D对分离的成年背根神经节神经元培养的轴突生长的直接影响。我们还将通过对正常或维生素D缺乏的大鼠的神经节和骨骼肌进行外植体培养，并评估肌肉调节轴突生长的能力，来检验靶组织的作用。这些研究首次系统地探讨了维生素D缺乏引起肌肉疼痛的生物学基础。他们也是第一个研究维生素D在成熟轴突生长中的作用的人。这项探索性研究的结果将为使用大鼠模型进行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作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缺乏在美国人群中普遍存在，临床研究表明两者之间存在因果关系。然而，维生素D缺乏导致肌肉疼痛的生物学基础尚不清楚。我们建议对维生素D缺乏导致肌肉疼痛的细胞机制进行第一次系统研究。这些研究将为使用维生素D补充剂作为预防或治疗方法来解决每年给美国经济造成超过400亿美元损失的问题提供基于证据的理由。

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.