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

• Applicants: Professorin Dr. Heide Siggelkow; Professor Dr. Mladen Vassilev Tzvetkov
• Subject Area: Endocrinology, Diabetology, Metabolism ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315858031

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.

• DFG Programme: Research Grants