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

描述(由申请人提供)： 骨质疏松症是一种重要的老年病。健康和经济负担 由这种疾病造成的影响是巨大的。无能为力的疼痛，身高下降和 骨质疏松性骨折的后果往往是毁灭性的，导致损失。 独立运作，甚至死亡。随着人口老龄化，努力 用非药物和药物手段预防骨质疏松性骨折 都是极其重要的。 最近，相当多的注意力集中在理解细胞 骨质疏松症中骨丢失的发生机制。有证据表明， 甲状旁腺激素(PTH)在调节这一现象中起着重要作用。 甲状旁腺激素通过刺激促吸收因子的产生而导致骨骼矿物质的丢失 全身或局部骨骼微环境中的细胞因子。工作 来自我们实验室的研究表明，白细胞介素6(IL-6)在 体内介导甲状旁腺激素的吸收作用。我们的研究重点是 甲状旁腺激素对IL-6及其可溶性受体表达的调节作用 以及PTH-IL-6轴在骨质疏松发病机制中的作用。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是甲状旁腺激素诱导骨吸收的必需下游介质 甲状旁腺素活性增强的状态。我们假设IL-6是一种重要的 甲状旁腺素在骨和雌激素缺乏性骨吸收中的中介作用 状态下，PTH依赖的IL-6的产生被夸大了。到目前为止，我们的数据支持 假设甲状旁腺激素引起的骨骼敏感性增加 雌激素缺乏状态是由甲状旁腺素诱导的IL-6产生增加所介导的。 为了继续研究这一假说，我们将：1.考察新形成的 甲状旁腺素输注后吸收反应的种族差异假说 在绝经后妇女中，是由于甲状旁腺素诱导的不同程度的 产生促进吸收的细胞因子。我们还将继续我们的研究，如 之前在K08奖(K08 DK02596)中提出：2.确定是否 体内中和IL-6阻断甲状旁腺激素诱导的小鼠骨丢失以及IL-6是否 基因敲除的小鼠不会因为甲状旁腺激素而失去骨骼。我们还将探索 卵巢切除对甲状旁腺激素诱导的骨吸收的影响 老鼠。3.研究甲状旁腺激素诱导的脑内钙离子浓度升高的分子机制 骨细胞产生IL-6及雌激素对其的调节作用 进程。

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.