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

在75岁的人群中，骨质疏松症的患病率为50%，是老年人生活障碍的主要原因之一。据估计，50%至80%的骨矿物质密度（BMD）变化是由基因决定的。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 - hsd1）基因多态性与骨质疏松症患者骨密度和骨折发生率之间的关联。在我们的研究中，携带rs11811440多态性a等位基因的老年骨质疏松患者的骨密度显著提高（t评分提高0.8）。这些影响比先前报道的骨质疏松症已知危险基因的遗传多态性的影响要强得多。该项目应该在未来的环境中验证和深化这些发现，更重要的是，应该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阶段，每个阶段都侧重于不同的战略目标。1级（分子生物学水平）应揭示11β - hsd1基因5内含子rs11811440等多态性影响基因表达和活性的机制。2级（细胞生物学水平）应该揭示11β - hsd1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。Level 3（临床水平）是一项针对骨质疏松症患者的前瞻性临床研究，旨在揭示11β - hsd1基因多态性与骨密度、肌肉功能和骨折发生率之间的关系。将分析一部分患者的多态性对组织形态计量学的影响，特别是关于骨髓中的脂肪。我们预计，携带rs11811440 SNP（或11β - hsd1中其他功能相关和遗传相关多态性）的纯合子a等位基因携带者将表现出最低的皮质醇水平、更少的骨髓脂肪、最高的骨密度、最佳的肌肉功能和最低的骨折率。我们希望通过证明rs11811440 SNP（或11β - hsd1中其他功能相关和遗传相关的多态性）影响11β - hsd1的表达，改变骨祖细胞中可皮质醇与皮质醇的比例，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11β - hsd1基因多态性作为风险评估的有价值标记，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骨质疏松症风险的遗传和非遗传变异性的多项进一步研究。

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.