MAGNESIUM DEFICIENCY INDUCED OSTEOPOROSIS

本建议的目的是增加我们对镁（Mg）损耗在骨质疏松症病因学中的作用的理解。膳食镁的摄入与骨量和/或骨质流失在衰老和绝经后骨质疏松症有关。Mg在大鼠体内的消耗导致骨生长减少、骨质减少和骨骼脆性增加。在缺镁大鼠中观察到骨形成减少和骨吸收增加。我们假设镁的消耗导致骨质疏松症的发生。镁缺乏对骨骼不良影响的机制尚不清楚，但可能与调节骨细胞活性的全身激素或局部因素有关。人体缺镁会导致低钙血症、低血清1,25(OH)2-维生素D水平、甲状旁腺激素（PTH）分泌受损以及肾脏和骨骼对PTH的抵抗。在动物模型中，Mg的消耗也显示了类似的结果。然而，镁缺乏的大鼠与其他物种不同，出现高钙血症而不是低钙血症。因此，对缺镁大鼠骨骼和矿物质代谢变化的推断不能用于人类。需要一种不同的缺镁所致骨质疏松症模型。我们建议建立衰老雌性小鼠缺镁所致骨质疏松模型。我们将诱导膳食缺镁3周和6周，并评估血清Mg、钙和甲状旁腺激素的变化。测定骨组织形态学及骨镁、钙、磷含量。细胞因子与骨质疏松症的发展有关，并且已知镁缺乏大鼠的血清水平较高。因此，我们将测量血清中I1-1 β和TNFalpha的水平，并对骨进行I1-1 β、I1-6的免疫组织化学染色。和TNFalpha。这些研究应证实我们的假设，即镁缺乏有助于骨质疏松症和探索可能的机制。如果得到证实，未来的实验将提出进一步确定确切的机制。该结果可能对骨质疏松症的预防具有重要意义。

The objective of this proposal is to increase our understanding of the role of magnesium (Mg) depletion in the etiology of osteoporosis. Dietary Mg intake has been associated with bone mass and/or bone loss in aging and postmenopausal osteoporosis. Mg depletion in the rat results in decreased bone growth, osteopenia and increased skeletal fragility. Decreased bone formation and increased bone resorption has been observed in the Mg depleted rat. We hypothesize that Mg depletion results in the development of osteoporosis. Mechanism(s) for the adverse effect of Mg deficiency on the skeleton is unclear but may involve systemic hormones or local factors regulating bone cell activity. Mg depletion in humans results in hypocalcemia, low serum 1,25(OH)2-vitamin D levels and impaired parathyroid hormone (PTH) secretion as well as renal and skeletal resistance to PTH. Mg depletion in animal models shows similar findings. The Mg deficient rat however, unlike other species, develops hypercalcemia rather than hypocalcemia. Extrapolation of alterations in bone and mineral metabolism in the Mg deficient rat cannot therefore be made to humans. A different model of Mg deficiency-induced osteoporosis is needed. We propose to develop a model of Mg deficiency-induced osteoporosis in the aging female mouse. We will induce dietary Mg deficiency for 3 and 6 weeks and assess changes in serum Mg, calcium and PTH. Bone histomorphometry and bone Mg, calcium and phosphorous content will be evaluated. Cytokines are implicated in the development of osteoporosis and serum levels are known to be high in the Mg deficient rat. We will therefore measure serum levels of I1- 1beta and TNFalpha and perform immunohistochemical staining of bone for I1-1beta, I1-6. And TNFalpha. These studies should substantiate our hypothesis that Mg depletion contributes to osteoporosis and explore possible mechanisms. If substantiated, future experiments will be proposed to further define exact mechanisms. The results may have important implications on the prevention of osteoporosis.