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衰老疾病。年龄别发病率 骨质疏松症是一种重要的衰老疾病。特定年龄 该疾病的发病率呈稳定或上升趋势，并且当这两者结合起来时 由于高危人群中美国老年人的数量较多， 很明显，在可预见的时间内，这种疾病的患病率将会上升 未来。每年已有近百万人发生骨折 65岁以上，其中绝大多数是由于 骨质疏松症。骨质疏松症是由于其他方面的永久性丧失造成的 骨骼中的正常骨骼。在这种疾病的各种亚型中， 绝经后骨质疏松症是迄今为止最常见的。骨质增加 吸收是绝经后骨质流失的主要机制 骨质疏松症，最近的证据表明骨吸收率 是老年人骨量的重要预测因子。 甲状旁腺激素（PTH）是骨吸收的主要调节因子 日复一日，对 PTH 的敏感性增加可能是 骨质疏松症中骨吸收增加。我们已经证明了 促吸收细胞因子 IL-6 在体外和体内均受 PTH 调节 体内并在介导 PTH 的再吸收作用中发挥着至关重要的作用。 因此，我们最近表明 IL-6 的循环水平升高 甲状旁腺功能亢进，甲状旁腺功能低下，并且 与患者骨吸收标志物密切相关 原发性甲状旁腺功能亢进症。在实验动物中，我们已经证明 PTH 输注会导致血清 IL-6 水平升高，并且中和 IL-6 抗血清可阻断 PTH 诱导的骨吸收增加。最后， 在培养的骨细胞和小鼠中，我们已经证明雌激素 停药会增加响应 PTH 的 IL-6 产量。我们假设 IL-6 是 PTH 在骨骼和组织中的再吸收作用的重要介质 在雌激素缺乏状态下，PTH 依赖性 IL-6 的产生 增加。 为了检验这个假设：（1）我们将检验 绝经后妇女在雌激素之前和之后输注 PTH 替代，以确定雌激素是否影响 PTH 诱导的 IL-6 变化。 (2) 我们将确定体内中和IL-6是否可以阻断PTH诱导的 小鼠骨质流失以及 IL-6 敲除小鼠是否不会出现骨质流失 对 PTH 的反应，我们还将检查卵巢切除术是否会增强 PTH 诱导的 骨质流失和 PTH 诱导小鼠循环 IL-6 增加。 (3) 我们 将研究PTH诱导IL-6增加的分子机制 骨细胞的产生以及雌激素对此的调节作用 过程。

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.