IL-6 AND ESTROGEN AND PTH INDUCED BONE RESORPTION

IL-6 和雌激素及 PTH 诱导的骨吸收

• 批准号: 6516715
• 负责人: URSZULA S MASIUKIEWICZ
• 金额: $ 13.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-15 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516715
• 关键词: blood chemistry; bone density; clinical research; densitometry; estrogens; female; gene targeting; genetically modified animals; hormone regulation /control mechanism; hormone therapy; human subject; human therapy evaluation; injection /infusion; interleukin 6; laboratory mouse; osteocytes; osteoporosis; ovariectomy; parathyroid hormones; pathologic bone resorption; postmenopause; urinalysis; women's health

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.

描述（摘自申请人摘要）： 骨质疏松症是一种重要的衰老性疾病。年龄别发病率 骨质疏松症是一种重要的衰老性疾病。年龄别 疾病的发病率是稳定的或增加的，当这是耦合 随着更多的美国老年人在风险人口中， 很明显，在可预见的未来， 未来每年有近100万人骨折 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永久性的损失，否则 正常的骨头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。增加的骨 骨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指标。 甲状旁腺激素（PTH）是骨吸收的主要调节因子， 对PTH的敏感性增加可能是 在骨质疏松症中观察到骨吸收增加。我们已经证明 促再吸收细胞因子IL-6在体外和体内受PTH调节， 在体内，并在介导PTH的再吸收作用中起关键作用。 因此，我们最近发现，循环中IL-6水平升高， 在甲状旁腺过多的状态下，甲状旁腺功能低下， 与骨吸收标志物密切相关， 原发性甲状旁腺功能亢进在实验动物中，我们已经证明 PTH输注导致血清IL-6水平升高， IL-6抗血清阻断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 戒断增加了响应PTH的IL-6产生。我们假设 IL-6是PTH在骨中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 增大 为了验证这一假设：（1）我们将检查 绝经后妇女在雌激素治疗前后输注PTH 替代，以确定雌激素是否影响PTH诱导的IL-6变化。 (2)我们将确定是否中和IL-6在体内阻断PTH诱导的 小鼠的骨丢失以及IL-6敲除小鼠是否不会骨丢失， 对PTH的反应，我们还将检查卵巢切除术是否增加PTH诱导的 骨丢失和PTH诱导的小鼠循环IL-6增加。(3)我们 将研究PTH诱导IL-6升高的分子机制 以及雌激素对此的调节作用 过程