IL-6 AND ESTROGEN AND PTH INDUCED BONE RESORPTION

描述(摘自申请人的摘要)： 骨质疏松症是一种重要的老年病。各年龄段发病率 骨质疏松症是一种重要的老年病。特定于年龄的 疾病的发病率是表或增加的，当这两者结合在一起时 随着高危人群中更多的老年美国人，它 很明显，在可预见的情况下，这种疾病的流行率将会上升 未来。每年已有近100万人发生骨折。 65岁以上，其中绝大多数是由于 骨质疏松。骨质疏松症是由于其他方面的永久性丧失造成的 骨骼上的正常骨骼。在这种疾病的各种亚型中， 绝经后骨质疏松症是目前最常见的。骨量增加 吸收是绝经后骨丢失的主要机制 骨质疏松症，最近的证据表明，骨吸收的速度 是预测老年人骨量的重要指标。 甲状旁腺激素(PTH)是骨吸收的主要调节因子 在日常生活的基础上，对甲状旁腺素的敏感性增加可能是 骨质疏松症患者骨吸收增加。我们已经证明了 促吸收细胞因子IL-6在体外和体内均受甲状旁腺素的调节 在调节甲状旁腺激素的吸收作用中起着关键作用。 因此，我们最近发现，循环中的IL-6水平升高 在甲状旁腺过度的状态下，甲状旁腺功能减退症的发生率较低，并且 骨质疏松症患者的骨吸收指标与骨吸收密切相关 原发性甲状旁腺功能亢进症。在实验动物中，我们已经证明 甲状旁腺素输注会导致血清IL-6水平升高，并中和 IL-6抗血清可阻断甲状旁腺素诱导的骨吸收增加。最后， 在培养的骨细胞和小鼠身上，我们都证明了雌激素 停药会增加甲状旁腺激素引起的IL-6的产生。我们假设 IL-6是甲状旁腺激素骨吸收作用的重要介质 在雌激素缺乏状态下，PTH依赖的IL-6的产生 增加。 为了检验这一假设：(1)我们将检查以下因素的反应 绝经后妇女在雌激素前后输注甲状旁腺素 替代，以确定雌激素是否影响甲状旁腺激素诱导的IL-6的变化。 (2)我们将确定体内中和IL-6是否能阻断PTH诱导的 小鼠的骨丢失和IL-6基因敲除小鼠是否没有骨吸收 对甲状旁腺激素的反应，我们还将检查卵巢切除是否增加甲状旁腺激素诱导 骨丢失和甲状旁腺素诱导小鼠循环中IL-6的增加。(3)我们 将研究甲状旁腺素诱导IL-6升高的分子机制 骨细胞产生及雌激素对其的调节作用 进程。

DESCRIPTION (Taken from the applicant's Abstract): Osteoporosis is an important disease of aging. The age-specific incidence of Osteoporosis is an important disease of aging. The age-specific incidence of the disease is table or increasing, and when this is coupled with the greater number of older Americans in the at risk population, it is clear that the prevalence of this disease will rise for the foreseeable future. Already nearly one million fractures occur annually in persons over the age of 65, and the vast majority of these are due to osteoporosis. Osteoporosis is due to the permanent loss of otherwise normal bone from the skeleton. Of the various subtypes of this disease, postmenopausal osteoporosis is by far the most common. Increased bone resorption is the principle mechanism for bone loss in postmenopausal osteoporosis, and recent evidence indicates that rates of bone resorption are important predictors of bone mass in older individuals. Parathyroid hormone (PTH) is the principle regulator of bone resorption on a day to day basis, and increasing sensitivity to PTH may underlie the increased bone resorption seen in osteoporosis. We have demonstrated that the pro-resorptive cytokine, IL-6, is regulated by PTH in vitro and in vivo and plays a crucial role in mediating the resorptive actions of PTH. Thus we have recently shown that circulating levels of IL-6 are elevated in states of parathyroid excess, are low in hypoparathyroidism, and correlate strongly with markers of bone resorption in patients with primary hyperparathyroidism. In experimental animals, we have demonstrated that PTH infusions cause serum IL-6 levels to rise and that neutralizing antisera to IL-6 block PTH-induced increases in bone resorption. Finally, in both cultured bone cells and mice, we have demonstrated that estrogen withdrawal increases IL-6 production in response to PTH. We hypothesize that IL-6 is an important mediator of PTH's resorptive actions in bone and that in the estrogen deficient state, PTH-dependent IL-6 production increases. To test this hypothesis: (1) We will examine the response of postmenopausal women to an infusion of PTH, before and after estrogen replacement, to determine if estrogen affects PTH-induced changes in IL-6. (2) We will determine whether neutralizing IL-6 in vivo blocks PTH-induced bone loss in mice and whether IL-6 knock-out mice do not lone bone in response to PTH, we will also examine if ovariectomy augments PTH-induced bone loss and PTH-induce increases in circulating IL-6 in mice. (3) We will study the molecular mechanism of the PTH-induced increase in IL-6 production by bone cells and the modulating effect of estrogen on this process.