IL-1 RECEPTOR ANTA IN OVARRIECTOMY INDUCED BONE LOSS

IL-1 受体 ANTA 在卵巢切除术引起的骨丢失中的作用

• 批准号: 3161845
• 负责人: ROBERTO PACIFICI
• 金额: $ 11.32万
• 依托单位: JEWISH HOSPITAL OF SAINT LOUIS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3161845
• 关键词: X ray; atomic absorption spectrometry; bone density; bone imaging /visualization /scanning; calcification; cytokine receptors; densitometry; enzyme linked immunosorbent assay; estrogens; female; gene expression; genetic transcription; genetic translation; inhibitor /antagonist; interleukin 1; laboratory rat; messenger RNA; normal ossification; northern blottings; nucleic acid hybridization; osteopetrosis; ovariectomy; pathologic ossification; postmenopause; radioimmunoassay; statistics /biometry

Studies from our and other laboratories suggest that Interleukin 1 (IL-1) may be implicated in the pathogenesis of postmenopausal osteoporosis and that the antiresorptive effect of estrogen may be related to its ability to regulate the secretion of this cytokine from mononuclear cells. Since these cells secrete numerous cytokines (TNFalpha, GM-CSF, M-CSF, and IL-6) which all exerts multiple and overlapping effects on bone, the specific role of IL-1 in postmenopausal bone loss remains to be established. A possible experimental strategy to determine if IL-1 has a direct role in postmenopausal bone loss is to block its secretion or its effects on bone. This proposal describes studies to be carried out in oophorectomized rats aimed to investigate the effects on bone mass and bone turnover of a systemic and local treatment with IL-1 receptor antagonist (IL-1ra), a substance which blocks IL-1 binding to IL-1 receptors. To this aim, we will monitor the changes in 1) bone density, as estimated by x-ray bone densitometry in vivo and by direct physical and chemical measurements of bone specimens in vitro, and 2) histological and biochemical indices of bone turnover. Control treatments will be 17Beta estradiol and the IL-1ra suspension medium. The systemic effects of IL-1ra will be determined by infusing all substances in the subcutaneous tissue with an Alzet osmotic pump. The local effects of IL-1ra will be determined by infusing this agent directly into the femur trabecular bone of oophorectomized rats with a small catheter as described by Yamamoto and Rodan, using the other limb as a control. Additional aims of the proposed studies will be to determine whether the regulatory effect of estrogen on IL-1 secretion takes place at the transcriptional or the translational levels and whether this effect is confined to blood cells or is exerted on bone marrow cells as well. If the bone loss and the increase in bone turnover associated with oophorectomy are prevented by treatment with IL-1ra, the data will provide a strong evidence that IL-1 is directly involved, at least in rats, in the bone loss caused by estrogen withdrawal. The potential significance of this project is high and may a) provide a direct evidence of an involvement of IL-1 in the pathogenesis of postmenopausal bone loss, b) lay a foundation for an alternative form of preventive or therapeutic intervention in postmenopausal bone loss and c) lead to the characterization of the mechanism by which estrogen regulated IL-1 secretion in mononuclear cells.

我们和其他实验室的研究表明，白细胞介素 1 (IL-1) 可能与绝经后骨质疏松症的发病机制有关 雌激素的抗吸收作用可能与其 调节单核细胞分泌该细胞因子。 自从 这些细胞分泌大量细胞因子（TNFα、GM-CSF、M-CSF 和 IL-6） 这些都对骨骼产生多重且重叠的影响，具体 IL-1 在绝经后骨质流失中的作用仍有待确定。 一个 确定 IL-1 是否具有直接作用的可能实验策略 绝经后骨质流失是指阻碍其分泌或其对骨骼的影响。 该提案描述了在卵巢切除大鼠中进行的研究 旨在研究骨量和骨转换的影响 使用 IL-1 受体拮抗剂 (IL-1ra) 进行全身和局部治疗， 阻断 IL-1 与 IL-1 受体结合的物质。 为了这个目标，我们 将监测 1) 骨密度的变化，通过骨 X 射线评估 体内密度测定法以及通过直接物理和化学测量 体外骨标本，2）组织学和生化指标 骨转换。 对照治疗为 17β 雌二醇和 IL-1ra 悬浮介质。 IL-1ra 的全身效应将由以下因素确定 将 Alzet 渗透剂注入皮下组织中的所有物质 泵。 IL-1ra 的局部效果将通过注入该物质来确定 药剂直接进入卵巢切除大鼠的股骨小梁 Yamamoto 和 Rodan 描述的小导管，使用另一肢 作为对照。 拟议研究的其他目标是确定 雌激素对IL-1分泌的调节作用是否发生在 转录或翻译水平以及这种效应是否是 仅限于血细胞或也作用于骨髓细胞。 如果 与卵巢切除术相关的骨质流失和骨转换增加 通过 IL-1ra 治疗可以预防这些疾病，该数据将提供强有力的证据 有证据表明 IL-1 至少在大鼠中直接参与骨质流失 雌激素戒断引起的。 该项目的潜在意义 是高的并且可能 a) 提供 IL-1 参与的直接证据 绝经后骨质流失的发病机制，b) 奠定基础 预防或治疗干预的替代形式 绝经后骨质流失和 c) 导致特征 雌激素调节单核细胞 IL-1 分泌的机制。