Revealing the influence of 11-beta-hydroxysteroid dehydrogenase (11β-HSD1) on bone fat content and bone quality in the context of genetics, aging, and inflammation

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

More than 20% of women aged above 50 years in Europe and 6% of men suffer from osteoporosis. The administration of exogenous glucocorticoids is a known risk factor for this. The role of endogenous cortisol is less well understood. We and others have reported associations between SNPs in the HSD11B1 gene and bone mineral density or fracture risk in osteoporosis patients. The HSD11B1 gene encodes the enzyme 11β-HSD1, which can convert inactive cortisone into active cortisol locally in the bone. In our first project phase, we developed HSD11B1 knockout and overexpressing SCP-1 cells. We used them together with an inhibition model of human mesenchymal stem cells (hMSCs) to analyze the influence of 11β-HSD1 on adipogenic and osteogenic differentiation. In addition, we conducted a prospective clinical study to investigate the effects of HSD11B1 polymorphisms on osteoporosis. We observed effects of HSD11B1 SNPs on peripheral cortisol synthesis and bone quality only in patients over 65 years of age, but not in younger patients. These observations, along with current findings in the literature about the role of 11β-HSD1 in inflammation and aging, prompted us to revise our initial hypothesis. We now propose that the ability of 11β-HSD1 to locally re-activate cortisone is an important modulator of inflammation in bones during aging. Therefore, the HSD11B1 genotype manifests through lifelong changes in 11β-HSD1 activity. These changes, driven by inflammation, occur within bone marrow adipose tissue (BMAT) and predominantly affect the bone phenotype in cases of secondary osteoporosis. To explore this hypothesis further, we plan to specifically analyze HSD11B1 genotypes in patients with secondary osteoporosis 65 years of age or older. In a subset of patients, preselected according to their HSD11B1 genotypes, we will perform in-depth analyses of BMAT using MRI. These will be complemented by ex vivo analyses of bone biopsies obtained intraoperatively from both young and old individuals. There, we will investigate the effects of 11β-HSD1 expression and HSD11B1 genotype on local cortisol levels, inflammatory markers, BMAT content and bone quality. On a cellular level, we plan to develop 2D and 3D multicellular models. Genetically modified SCP-1 cells, as well as primary hMSCs, will be used in these models to analyze BMAT formation and bone remodeling as functions of 11β-HSD1 expression and genotype. The age of the donors will be taken into account, and inflammation conditions will be simulated. On a molecular level, we will perform high-throughput RNA expression and chromatin accessibility analyses in the HSD11B1 knockout and overexpressing SCP-1 cells, as well as in hMSCs, to explore the global effects of 11β-HSD1 during cell differentiation.

• DFG Programme: Research Grants