Glucocorticoid-Effekte auf die osteohämatopoetische Nische
Zusammenfassung der Projektergebnisse
Glucocorticoids (GC) are potent immunsuppressive agents. Due to their immunmodulating properties, GC are still frequently used in the treatment of inflammatory disorders. However, GC exert also severe side effects, among others, on bone turnover. GC act via the glucocorticoid receptor (GR) and thereby modulate expression of their target genes. We investigated in this project how GC applied in therapeutic doses affect hematopoietic stem cells (HSCs) and the osteohematopoietic niche in the bone marrow. As expected, flow cytometry analyses in wild type mice showed that GC treatment for 4 weeks applied via the drinking water reduced the number and frequency of HSCs in the bone marrow. The underlying cause for the reduced HCS numbers was a higher apoptosis rate in HSCs derived from GC treated mice. With the help of bone marrow transplantations of HSCs from GC-treated mice that were transplanted to lethally irradiated wild type mice, we found that therapeutic doses of GC increase the repopulation ability of HSCs. These results were somehow unexpected and indicate that the function of HSCs is improved after long-term GC therapy. Furthermore, extensive analyses of GR-deficient mice showed that GC exert their HSC modulating effects directly via the GR in HSCs. Currently, we are investigating the underlying mechanisms of GC effects on HSCs in more detail. For this purpose, we sorted HCSs from the bone marrow of GC treated mice and isolated RNA for sequencing analyses. The results of this study could be recently presented at the annual congress of the “European Calcified Tissue Society (ECTS)” in Marseille, France. Future studies that are based on the results of this project, will aim on the HSCs numbers and function derived from patients that received GC therapy. Furthermore, we hope to get a better understanding of the underlying mechanisms in more detail with future experiments.
Projektbezogene Publikationen (Auswahl)
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Bad to the Bone: The Effects of Therapeutic Glucocorticoids on Osteoblasts and Osteocytes. Frontiers in Endocrinology, 13.
Gado, Manuel; Baschant, Ulrike; Hofbauer, Lorenz C. & Henneicke, Holger
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Activation of β-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice. American Journal of Physiology-Endocrinology and Metabolism, 324(6), E514-E530.
Gado, Manuel; Heinrich, Annett; Wiedersich, Denise; Sameith, Katrin; Dahl, Andreas; Alexaki, Vasileia I.; Swarbrick, Michael M.; Baschant, Ulrike; Grafe, Ingo; Perakakis, Nikolaos; Bornstein, Stefan R.; Rauner, Martina; Hofbauer, Lorenz C. & Henneicke, Holger
