Role of IL-6 and estrogen in PTH-induced bone resorption

IL-6和雌激素在PTH诱导的骨吸收中的作用

• 批准号: 6465741
• 负责人: URSZULA S MASIUKIEWICZ
• 金额: $ 8.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6465741
• 关键词: African American; caucasian American; estrogens; female; genetically modified animals; hormone regulation /control mechanism; human subject; interleukin 6; laboratory mouse; osteoporosis; ovariectomy; parathyroid hormones; pathologic bone resorption; patient oriented research; postmenopause; racial /ethnic difference

DESCRIPTION (provided by applicant): Osteoporosis is an important disease of aging. The health and economic burdens imposed by this disease are enormous. Incapacitating pain, loss of height and consequences of osteoporotic fracture are often devastating, resulting in loss of independent function or even death. As the population ages efforts to prevent osteoporotic fractures by non-pharmacological and pharmacological means are of utmost importance. Considerable attention has focused recently on understanding the cellular mechanisms by which bone loss occurs in osteoporosis. Evidence indicates that parathyroid hormone (PTH) has an important role in mediating this phenomenon. PTH causes loss of skeletal mineral by stimulating production of pro-resorptive cytokines either systemically or locally in the bone microenvironment. Work from our laboratory has suggested a critical role for interleukin-6 (IL-6) in mediating the resorptive effects of PTH in vivo. The focus of our research has been on PTH-dependent regulation of IL-6 and IL-6 soluble receptor expression and the role of the PTH-IL-6 axis in the pathogenesis of osteoporosis. A series of animal and human studies completed by our group indicate, in aggregate, that IL-6 is a required down-stream mediator of bone resorption induced by PTH in states of enhanced PTH activity. 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 is exaggerated. To date our data support the hypothesis that the increased skeletal sensitivity to PTH in the estrogen-deficient state is mediated by augmented PTH-induced IL-6 production. To continue to study this hypothesis we will: 1. Examine the newly formed hypothesis that racial differences in the resorptive response to PTH infusion in postmenopausal women, are due to differential PTH-induced increases in the production of pro-resorptive cytokines. We will also continue our studies as previously proposed in K08 Award (K08 DK02596) to: 2. Determine whether neutralizing IL-6 in vivo blocks PTH-induced bone loss in mice and whether IL-6 knock-out mice do not lose bone in response to PTH. We will also explore the effect of ovariectomy on PTH-induced bone resorption in wild type and knock-out mice. 3. Examine the molecular mechanism underlying PTH-induced increases in IL-6 production by bone cells and the modulating effect of estrogen on this process.

描述（由申请人提供）： 骨质疏松症是一种重要的衰老性疾病。健康和经济负担 是巨大的。丧失能力的疼痛，身高下降， 骨质疏松性骨折的后果往往是毁灭性的， 独立运作甚至死亡随着人口老龄化， 通过非药物和药物手段预防骨质疏松性骨折 至关重要 最近，相当多的注意力集中在理解细胞的 骨质疏松症中骨丢失的发生机制。证据表明 甲状旁腺激素（PTH）在介导这种现象中具有重要作用。 甲状旁腺素通过刺激促骨吸收蛋白的产生而导致骨骼矿物质的损失。 细胞因子全身或局部地在骨微环境中。工作 我们实验室的研究表明，白细胞介素-6（IL-6）在 介导体内甲状旁腺激素的再吸收作用。我们研究的重点是 对PTH依赖性调节IL-6和IL-6可溶性受体表达的研究 以及PTH-IL-6轴在骨质疏松症发病机制中的作用。一系列 我们小组完成的动物和人类研究表明，总的来说， IL-6是PTH诱导骨吸收的下游介质， PTH活性增强的状态。我们假设IL-6是一种重要的 PTH的骨吸收作用的介质和雌激素缺乏 因此，PTH依赖性IL-6产生被夸大。我们的数据支持 这一假说认为，在老年人中，骨骼对PTH的敏感性增加， 雌激素缺乏状态是由PTH诱导的IL-6产生增加介导的。 为了继续研究这个假设，我们将：1。检查新形成的 PTH输注吸收反应种族差异假说 在绝经后妇女中，是由于不同的PTH诱导的增加， 促再吸收细胞因子的产生。我们也将继续我们的研究， 先前在K 08裁决（K 08 DK 02596）中提出：2.确定是否 体内中和IL-6阻断小鼠PTH诱导的骨丢失， 敲除小鼠不会响应于PTH而丢失骨。我们亦会探讨 卵巢切除对野生型和基因敲除型PTH诱导骨吸收的影响 小鼠3.检查PTH诱导的细胞凋亡增加的分子机制。 骨细胞产生IL-6及雌激素的调节作用 过程