GLUOCORTICOIDS, OSTEOCYTES, AND BONE STENGTH IN AGE-RELATED OSTEOPOROSIS

年龄相关性骨质疏松症中的糖皮质激素、骨细胞和骨强度

• 批准号: 7628477
• 负责人: ROBERT Stewart WEINSTEIN
• 金额: $ 26.16万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7628477
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Ablation; Adrenal Glands; Adverse effects; Affect; Age; Age-Months; Age-Related Bone Loss; Aging; Americas; Amplifiers; Anoikis; Apoptosis; Biomechanics; Blood Circulation; Bone Density; Bone Resorption; C57BL/6 Mouse; Caspase; Cells; Cessation of life; Detection; Deterioration; Diphtheria Toxin; Enzymes; Exhibits; Extracellular Matrix; Focal Adhesion Kinase 1; Focal Adhesions; Fracture; Glucocorticoid Receptor; Glucocorticoids; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; In Vitro; Investigation; KRP protein; Longevity; Mediating; Modeling; Mus; Nutrient; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Prevalence; Prevention; Production; Property; Protein Overexpression; Proteins; Rate; Research Personnel; Risk; Role; Signal Transduction; Skeletal system; Skeleton; Spinal; Study Section; Testing; Tissues; Transgenic Animals; Transgenic Mice; Work; age related; base; bisphosphonate; bone; bone cell; bone loss; bone quality; bone strength; dentin matrix protein 1; diphtheria toxin receptor; falls; in vivo; innovation; mature animal; promoter; protein tyrosine kinase PYK2; receptor; repaired; spine bone structure; stress-activated protein kinase 1; tartrate-resistant acid phosphatase; wasting

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.

基于发现糖皮质激素诱导的骨强度损失的发现，部分原因是 骨细胞的死亡与骨质流失无关，以及皮质醇水平以及局部组织的证据 小鼠和人类的糖皮质激素作用的扩增随着年龄的增长而增加，这是一个假设，即 随着衰老而发生的骨强度和质量之间的差异部分是由于不良骨骼 内源性糖皮质激素的影响将测试。糖皮质激素作用的这种增强将 导致骨细胞凋亡的患病率和破骨细胞寿命的延长。 糖皮质激素对这些细胞的作用是由涉及富含脯氨酸酪氨酸的非核酸机制引起的 激酶2（PYK2）激活。随后的糖皮质激素诱导的骨细胞凋亡对骨骼产生负面影响 通过破坏管道循环，降低材料特性的强度，允许积累 骨骼受损，或所有三个。为了检验该假设，在AIM 1中，骨骼损失之间的对比度 野生型和转基因小鼠的矿物密度（BMD）和8、16和25个月大的强度 过表达的113-羟基固醇脱氢酶2型，一种使糖皮质激素失活的酶 受体前的时尚将被确定。这将在 骨钙素启动子（因此保护骨细胞和成骨细胞免受糖皮质激素的作用）或 抗性抗酸性磷酸酶启动子的控制（从而保护破骨细胞免受糖皮质激素 动作）。在AIM 2中，局灶性粘附相关蛋白Pyk2的作用在相反的作用中 将描绘在骨细胞和破骨细胞寿命上的糖皮质激素。具体而言，那些对立的效果 是诱导骨细胞凋亡和预防破骨细胞凋亡。在AIM 3中，贡献 骨细胞对骨强度的细胞凋亡将通过诱导快速的条件骨细胞消融来确定 通过凋亡使用毒素毒素给药和牙本质基质蛋白1启动子控制 小鼠的白喉毒素受体是一种原本对白喉毒素不敏感的物种。创新研究 在该项目中提出的建议将通过描述内生的贡献来扩展以前的工作 糖皮质激素对影响老化骨骼的多因素损害。这个项目的重要性是 随着美国衰老而发生的骨质疏松症负担的增加而扩大。老年人 对糖皮质激素的不良骨骼影响更敏感，该项目将提供详细的 研究其肾上腺产生的糖皮质激素如何导致AGJNG裂缝 骨骼。