MARROW BIOLOGY AND BONE MASS--EFFECTS OF AGE AND HORMONE

骨髓生物学和骨量——年龄和激素的影响

• 批准号: 2053766
• 负责人: JULIANNE GLOWACKI
• 金额: $ 33.08万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2053766
• 关键词: aromatase; biology; bone density; bone fracture; bone marrow; bone metabolism; cytokine; disease /disorder proneness /risk; estrogens; gene expression; hormone biosynthesis; human tissue; human very old age (85+); normal ossification; osteoclasts; osteogenesis; osteopenia; osteoporosis; postmenopause; skeletal pharmacology; tissue /cell culture; women's health

DESCRIPTION: (Adapted From Investigator's Abstract) Osteoporosis is a major women's health problem in the postmenopausal period and also in extreme old age. Estrogen prevents bone loss, with recent data suggesting that estrogens directly suppress cytokine-mediated osteoclast differentiation and bone resorption. Circulating estrogen levels, however, do not distinguish normal postmenopausal from osteoporotic women, but there are data showing that serum levels of the adrenal steroidal precursor, dehydroepiandrosterone sulfate (DHEAS) are lower in osteoporotics.Increased body weight and fat, moreover, are protective of bone after menopause. In postmenopausal women, adipose tissue is the main site of estrogen production.It is possible that fat in marrow as well may provide a source of estrogen that exerts a paracrine effect on bone metabolism. The overall goal of this proposal is to determine whether differences in marrow biology play a role in the pathophysiology of osteoporosis. The applicants have established a new cell culture system using bone marrow harvested from discarded femurs at the time of total hip replacement. Marrow biosynthesis of estrogen, aromatase expression, cytokine production, and osteoclastogenesis will be assessed in vitro for normal (traumatic fracture) and osteoporotic women who come to surgery.Trabecular bone samples taken from the surgical site will be examined for osteoclast number. Subjects will be characterized for bone mineral density (BMD), body fat, and serum steroid levels, and will be controlled for risk factors associated with osteopenia. Specific Aim I will test the hypothesis that women with reduced bone density or osteoporotic fractures will show low estrogen production by marrow. The investigators will measure aromatase mRNA expression and estrogen synthesis in marrow from osteoporotic and age-matched, nonosteoporotic women who present for surgery. They will relate substrate availability, [DHEAS], to these measures. They will also determine whether there are correlations between marrow estrogen production and BMD or body fat.In Specific Aim II the applicants will test the hypothesis that cytokine production and osteoclastogenesis in vitro are elevated in marrow from osteoporotic women and are correlated with BMD and body fat composition, marrow estrogen biosynthesis, and osteoclast count in trabecular bone. In Specific Aim III they will test the hypothesis that cytokine production and osteoclastogenesis can be modulated by estrogen, DHEA[S], or androgen in vitro. The resulting information would represent a major step in understanding the pathogenesis of osteoporosis and why some women do to not show increased bone loss and fractures with age.

描述：（改编自研究者摘要）骨质疏松症是一种 绝经后妇女的主要健康问题， 极端高龄 雌激素可防止骨质流失，最新数据 表明雌激素直接抑制了马槟榔碱介导的破骨细胞 分化和骨吸收。 循环雌激素水平， 然而，不能区分正常绝经后与绝经后 女性，但有数据显示，血清肾上腺素水平， 类固醇前体硫酸脱氢表雄酮（DHEAS）较低 此外，体重和脂肪的增加也具有保护作用， 绝经后的骨质疏松 在绝经后妇女中，脂肪组织是 雌激素产生的主要场所。骨髓中的脂肪可能是 以及可能提供雌激素的来源，对 骨代谢 本提案的总体目标是确定 骨髓生物学的差异是否在病理生理学中起作用 骨质疏松症 申请人已经建立了一种新的细胞培养 系统使用的骨髓从废弃的股骨时， 全髋关节置换术 骨髓合成雌激素，芳香化酶 将评估细胞因子表达、细胞因子产生和破骨细胞生成 在体外为正常（创伤性骨折）和骨质疏松症的妇女谁来 从手术部位采集的骨小梁样本将被 检查破骨细胞数量。 将对受试者的骨进行表征 矿物质密度（BMD）、体脂和血清类固醇水平，并将 控制与骨质减少相关的风险因素。 具体目标我将检验骨质减少的女性 高密度骨折或骨质疏松性骨折将显示低雌激素产生， 骨髓 研究人员将测量芳香化酶mRNA的表达， 骨髓中雌激素的合成， 接受手术的非骨质疏松女性。 他们将与 底物可用性，[DHEAS]，这些措施。 他们还将 以确定骨髓雌激素 生产和骨密度或身体脂肪。在具体目标II，申请人将 测试细胞因子的产生和破骨细胞的生成在 体外培养的人骨髓中的钙离子浓度升高， 与BMD和体脂组成，骨髓雌激素生物合成， 骨小梁中破骨细胞计数。 在《特定目标3》中，他们将测试 细胞因子的产生和破骨细胞的生成可能是 在体外由雌激素、DHEA [S]或雄激素调节。 所得 信息将是了解 骨质疏松症的发病机制和为什么有些妇女不显示增加 骨质流失和骨折。