Magnesium Deficiency: Effect on Bone and Mineral

这项建议的目的是增加我们对镁缺乏在骨质疏松症病因中的作用的了解。虽然性激素缺乏是绝经后骨质疏松症的主要因素，但营养也很重要。膳食镁摄入量与衰老和绝经后骨质疏松症的骨量有关。镁缺乏的疾病，如酒精中毒、吸收不良综合征和糖尿病，也会增加患骨质疏松症的风险。女性的平均膳食镁摄入量是RDA的68%，这表明我国人口中有很大一部分人存在严重的膳食镁缺乏。严重的镁缺乏会导致大鼠骨生长受损、骨量减少和骨骼脆性。导致大鼠或人类骨质疏松症的饮食镁摄入量水平尚不清楚。在我们的提案中，我们将在大鼠中分别采用推荐营养需要量的10%、25%和50%的饮食镁剥夺。这种镁摄入量的减少反映了我们人口中饮食镁不足的水平。我们的第一个具体目标是确定将导致骨镁含量评估的镁缺乏的饮食摄入量。另一个具体目标是评估这些膳食镁摄入量对骨组织学、组织形态计量学和骨转换的影响；即。骨质疏松症发生在镁摄入量的什么水平，它是否反映在成骨细胞和破骨细胞活动的改变上。先前观察到的严重缺镁导致骨质疏松症的机制尚不清楚，但可能涉及全身激素或局部调节骨细胞活动的因素。人和大鼠严重缺镁导致血清甲状旁腺激素(PTH)和1，25(OH)2-维生素D降低，这可能是导致骨形成减少的原因之一。我们将通过测定血清钙、甲状旁腺素和1，25(OH)2-维生素D水平来量化低镁摄入量对钙稳态的影响。严重缺镁患者破骨细胞性骨吸收增加的原因尚不清楚。细胞因子可增加破骨细胞性骨吸收，并与绝经后骨质疏松症有关。镁缺乏会导致大鼠血清P物质增加，进而刺激各种细胞因子的产生。因此，我们将检测镁缺乏大鼠的血清P物质、肿瘤坏死因子α、白介素1β和白介素6，并对这些细胞因子进行骨免疫组织化学染色。将进行平行研究，使用一种特定的P物质受体抑制剂来直接测试这些细胞因子的产生是否与镁缺乏导致的骨丢失有关。这些研究应该证实我们的假设，即镁缺乏会导致骨质疏松症，并提供机制解释。

The objective of this proposal is to increase our understanding of the role of magnesium (Mg) deficiency in the etiology of osteoporosis. While sex steroid deficiency is a major factor in postmenopausal osteoporosis, nutrition is also important. Dietary Mg intake has been associated with bone mass in aging and postmenopausal osteoporosis. Disorders in which Mg deficiency is common such as alcoholism, malabsorption syndrome and diabetes also have an increased risk of osteoporosis. The average dietary Mg intake in women is 68 percent of the RDA indicating that a large proportion of our population have substantial dietary Mg deficits. Severe Mg deficiency in the rat results in impaired bone growth, osteopenia and skeletal fragility. The level of dietary Mg intake that results in osteoporosis in rat or human is unknown. In our proposal, we will employ dietary Mg deprivation in the rat at 10 percent, 25 percent, and 50 percent of recommended nutrient requirement. This reduction in Mg intake reflects levels of dietary Mg inadequacy in our population. Our first specific aim is to determine the dietary intake that will result in Mg deficiency as assessed by bone Mg content. Another specific aim is directed at assessing the effect of these dietary Mg intakes on bone histology, histomorphometry and bone turnover; ie. at what level of Mg intake does osteoporosis occur and is it reflected by alteration in osteoblast and osteoclast activity. The mechanism for the previously observed osteoporosis in severe Mg deficiency is unclear but may involve systemic hormones or local factors regulating bone cell activity. Severe Mg deficiency in humans and rats result in low serum parathyroid hormone (PTH) and 1,25(OH)2-vitamin D which may contribute to reduced bone formation. We will quantify the effects of low Mg intake on calcium homeostasis by determining serum calcium, PTH and 1,25(OH)2-vitamin D levels. The cause of increased osteoclastic bone resorption in severe Mg deficiency is unclear. Cytokines can increase osteoclastic bone resorption and are implicated in postmenopausal osteoporosis. Mg deficiency in the rat results in an increase in serum substance P which in turn stimulates production of various cytokines. We will therefore measure serum substance P, TNFalpha, IL1beta, and IL6 in the Mg deficient rat and perform immunohistochemical staining of bone for these cytokines. Parallel studies will be performed in which a specific substance P receptor inhibitor will be administered to directly test whether generation of these cytokines are responsible for Mg deficiency-induced bone loss. These studies should substantiate our hypothesis that Mg depletion contributes to osteoporosis and provide mechanistic explanations.