Effects of genetic polymorphisms in the 11-beta hydroxysteroid dehydrogenase (11beta-HSD1) on cortisol metabolism in bone:A step towards better understanding of individual risks of osteoporosis

11-β羟基类固醇脱氢酶（11β-HSD1）基因多态性对骨皮质醇代谢的影响：更好地了解骨质疏松症个体风险的一步

• 批准号: 315858031
• 负责人: Professorin Dr. Heide Siggelkow
• 金额: --
• 依托单位: Abteilung Allgemeine Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315858031?language=en
• 关键词: Effects; genetic; polymorphisms; 11; beta

With a prevalence of 50% at the age of 75 years osteoporosis is one of the leading reasons for live impairment in the elderly. It is estimated that 50 to 80% of variations in bone mineral density (BMD) is genetically determined. Two independent retrospective studies demonstrated associations between genetic polymorphisms in 11-beta hydroxysteroid dehydrogenase (11beta-HSD1), BMD and fracture rates in patients with osteoporosis. In our study, elderly osteoporosis patients, who were homozygous carriers of the A-allele of the rs11811440 polymorphism had substantial better BMD (a T-score improvement of 0.8). These effects were much stronger than previously reported effects of genetic polymorphisms in well known risk genes for osteoporosis. This project should validate and deepen these findings in a prospective setting, and more importantly, should reveal the molecular and cell biological mechanisms behind the observed association. The project consists of three experimental levels each focusing on a different strategic aim. Level 1 (the molecular biology level) should reveal the mechanisms by which rs11811440 and other polymorphisms in intron 5 of the 11beta-HSD1 gene affect gene expression and activity. Level 2 (the cell biology level) should reveal how changes in 11beta-HSD1 activity in general, and due to genetic polymorphisms in particular, affect cortisol metabolism and bone cell differentiation both in model cell lines and in patient-derived bone stem cells. Level 3 (the clinical level) is a prospective clinical study in osteoporosis patients aiming to show relationships between polymorphisms in 11beta-HSD1 gene and BMD, muscle function and fracture rates. A subset of the patients will be analyzed for effects of the polymorphisms on histomorphometry with special regard to fat in bone marrow. We expect that homozygous A-allele carriers of the rs11811440 SNP (or other functionally relevant and genetically linked polymorphisms in 11beta-HSD1) will show the lowest cortisol level, less fat in bone marrow, the highest BMD, the best muscle function, and the lowest fracture rates. We expect to explain these results by proving that the rs11811440 SNP (or other functionally relevant and genetically linked polymorphisms in 11beta-HSD1) influences 11beta-HSD1 expression, changes the cortisone to cortisol ratio in bone progenitor cells and affects bone-to-fat differentiation in bone marrow. With this project we intend to demonstrate that variations in the ability of bone to synthesize cortisol may affect the risk of osteoporosis. This project should establish genetic polymorphisms in 11beta-HSD1 as a valuable markers for risk assessment and will pave the way for an individualized diagnostic and therapy in osteoporosis. Beyond this the data and patient samples systematically collected in this project can be used for multiple further studies on genetic und non-genetic variability in risk for osteoporosis.

骨质疏松症在75岁时的患病率为50%，是老年人生活损害的主要原因之一。据估计，50%至80%的骨矿物质密度（BMD）的变化是由遗传决定的。两项独立的回顾性研究证实了11-β-羟基类固醇脱氢酶（11 β-HSD 1）基因多态性与骨质疏松症患者的BMD和骨折率之间的相关性。在我们的研究中，老年骨质疏松症患者，谁是纯合子携带者的A等位基因的rs 11811440多态性有显着更好的BMD（T评分改善0.8）。这些影响比以前报道的已知骨质疏松症风险基因中遗传多态性的影响强得多。该项目应在前瞻性环境中验证和深化这些发现，更重要的是，应揭示所观察到的关联背后的分子和细胞生物学机制。该项目包括三个实验级别，每个级别侧重于不同的战略目标。第1级（分子生物学水平）应揭示rs 11811440和11 β-HSD 1基因内含子5中的其他多态性影响基因表达和活性的机制。2级（细胞生物学水平）应揭示11 β-HSD 1活性的变化，特别是由于遗传多态性，如何影响模型细胞系和患者来源的骨干细胞中的皮质醇代谢和骨细胞分化。3级（临床水平）是一项在骨质疏松症患者中进行的前瞻性临床研究，旨在显示11 β-HSD 1基因多态性与BMD、肌肉功能和骨折发生率之间的关系。将分析一个患者子集的多态性对组织形态计量学的影响，特别是骨髓中的脂肪。我们预计rs 11811440 SNP（或11 β-HSD 1中其他功能相关和遗传连锁多态性）的纯合A等位基因携带者将显示最低的皮质醇水平，骨髓中的脂肪较少，BMD最高，肌肉功能最好，骨折率最低。我们希望通过证明rs 11811440 SNP（或11 β-HSD 1中其他功能相关和遗传连锁的多态性）影响11 β-HSD 1表达，改变骨祖细胞中可的松与皮质醇的比例，并影响骨髓中骨向脂肪的分化来解释这些结果。通过这个项目，我们打算证明骨骼合成皮质醇能力的变化可能会影响骨质疏松症的风险。该项目将建立11 β-HSD 1基因多态性作为风险评估的有价值的标志物，并为骨质疏松症的个体化诊断和治疗铺平道路。除此之外，本项目系统收集的数据和患者样本可用于进一步研究骨质疏松症风险的遗传和非遗传变异性。