Molecular, cellular and in vivo analyses of the effects of genetic polymorphisms in the 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) on peripheral cortisol metabolism in bone
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Book;
Hochschulschrift
Titel:
Molecular, cellular and in vivo analyses of the effects of genetic polymorphisms in the 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) on peripheral cortisol metabolism in bone
In Germany, around 5.7 million people suffer from osteoporosis. Osteoporosis is characterised by a reduced bone mineral density that leads to an increased risk of fractures. The 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is an important regulator of local cortisol metabolism. It converts biologically inactive cortisone to biologically active cortisol, but can also catalyse the reverse reaction. 11β-HSD1 is strongly expressed in liver, but 11β-HSD1 expression and activity were also reported in bone. Moreover, polymorphisms in intron 5 of HSD11B1 (the gene encoding for 11β-HSD1) are associated with bone mineral density (BMD) and risk of fractures. This work aimed to confirm and refine the associations between polymorphisms in intron 5 of HSD11B1 and BMD, and to identify the underlying molecular and cellular mechanisms. To this end, analyses were performed on three different levels: i) studies in humans, to confirm and refine the association of polymorphisms in intron 5 of HSD11B1 with BMD, suppressed cortisol levels (PDC) and stiffness index, ii) cellular analyses, to identify the role of 11β-HSD1 in differentiation of the immortalised human mesenchymal stem cell line SCP-1, iii) molecular genetic analyses, to reveal the effect of intron 5 polymorphisms on transcriptional regulation. Fine-mapping analyses of already existing clinical data from 452 osteoporosis patients (HSD study) did not point to another intron 5 SNP as being causative for the observed clinical association ...