GLUOCORTICOIDS, OSTEOCYTES, BONE STENGTH IN AGE-RELATED

糖皮质激素、骨细胞、年龄相关的骨强度

• 批准号: 7094998
• 负责人: ROBERT Stewart WEINSTEIN
• 金额: $ 17.14万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094998
• 关键词: Mus musculus; aging; apoptosis; biomechanics; bone density; bone fracture; cellular pathology; extracellular matrix proteins; focal adhesion kinase; genetically modified animals; glucocorticoids; molecular pathology; osteoblasts; osteoclasts; osteocytes; osteoporosis; prednisolone; skeletal pharmacology

Based on the discovery that glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes independent of bone loss, and evidence that cortisol levels as well as local tissue amplification of glucocorticoid action increase with age in both mice and humans, the hypothesis that the disparity between bone strength and mass that occurs with aging is due in part to the adverse skeletal impact of endogenous glucocorticoids will be tested. This enhancement of glucocorticoid effects would result in an increase in the prevalence of osteocyte apoptosis and prolongation of osteoclast lifespan. Glucocorticoid effects on these cells result from nongenotropic mechanisms involving proline-rich tyrosine kinase 2 (Pyk2) activation. The ensuing glucocorticoid-induced osteocyte apoptosis negatively affects bone strength by disrupting canalicular circulation, degrading material properties, allowing accumulation of damaged bone, or all three. To test this hypothesis, in Aim 1, the contrast in vivo between the loss of bone mineral density (BMD) and strength at 8, 16, and 25 months of age in wild-type and transgenic mice overexpressing 113-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids in a pre-receptor fashion, will be determined. This will be accomplished either under the control of the osteocalcin promoter (thus protecting osteocytes and osteoblasts from glucocorticoid action) or under control of the tartrate-resistant acid phosphatase promoter (thus protecting osteoclasts from glucocorticoid actions). In Aim 2, the role of the focal adhesion-related protein Pyk2 in the opposing effects of glucocorticoids on osteocyte and osteoclast lifespan will be delineated. Specifically, those opposing effects are the induction of osteocyte apoptosis and prevention of osteoclast apoptosis. In Aim 3, the contribution of osteocyte apoptosis to bone strength will be determined by inducing rapid, conditional osteocyte ablation via apoptosis using diphtheria toxin administration and the dentin matrix protein 1 promoter controlling the diphtheria toxin receptor in mice, an otherwise diphtheria toxin-insensitive species. The innovative studies proposed in this project will extend previous work by delineating the contribution of endogenous glucocorticoids to the multifactorial damages that affect the aging skeleton. The importance of this project is amplified by the increasing burden of osteoporosis that will occur with the aging of America. Older people are more sensitive to the adverse skeletal effects of glucocorticoids and this project will provide a detailed investigation of how the glucocorticoids produced by their adrenal glands contribute to fractures in the agjng skeleton.

基于糖皮质激素诱导的骨强度损失部分是由于 骨细胞的死亡与骨丢失无关，并且有证据表明皮质醇水平以及局部组织 在小鼠和人类中，糖皮质激素作用的放大随着年龄的增长而增加， 随着年龄的增长，骨强度和骨质量之间的不一致部分是由于骨骼的不利影响， 将测试内源性糖皮质激素的影响。这种糖皮质激素效应的增强将 导致骨细胞凋亡发生率增加和破骨细胞寿命延长。 糖皮质激素对这些细胞的作用是由涉及富含脯氨酸的酪氨酸的非遗传性机制引起的 激酶2（Pyk 2）活化。糖皮质激素诱导的骨细胞凋亡对骨产生负面影响 通过破坏泪小管循环，降低材料性能，允许 或者三个都有为了验证这一假设，在目标1中，在体内对比骨丢失与骨丢失之间的差异。 野生型和转基因小鼠在8、16和25月龄时的矿物质密度（BMD）和强度 过表达113-羟基类固醇脱氢酶2型，一种在哺乳动物中使糖皮质激素失活的酶， 前受体的方式，将被确定。这将是在控制下完成， 骨钙素启动子（从而保护骨细胞和成骨细胞免受糖皮质激素作用）或 控制抗酒石酸酸性磷酸酶启动子（从而保护破骨细胞免受糖皮质激素的影响 行动）。在目的2中，局灶性粘附相关蛋白Pyk 2在以下相反作用中的作用： 糖皮质激素对骨细胞和破骨细胞寿命的影响。具体来说，这些相反的效果 是诱导骨细胞凋亡和防止破骨细胞凋亡。在目标3中， 骨细胞凋亡对骨强度的影响将通过诱导快速、条件性骨细胞消融来确定 通过使用白喉毒素施用的细胞凋亡和牙本质基质蛋白1启动子控制细胞凋亡， 白喉毒素受体的小鼠，否则白喉毒素不敏感的物种。创新研究 在这个项目中提出的将扩展以前的工作，划定内源性的贡献， 糖皮质激素对影响衰老骨骼的多因素损伤的作用。该项目的重要性在于 随着美国老龄化的加剧，骨质疏松症的负担也会增加。老年人 对糖皮质激素对骨骼的不良影响更敏感，该项目将提供详细的 老年人肾上腺分泌糖皮质激素与骨折关系的研究 骷髅