The effect of glucocorticoid excess on the osteohematopoietic niche

• Applicants: Dr. Ulrike Baschant; Dr. Holger Henneicke, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415012230

Glucocorticoids (GCs) are potent immunosuppressive drugs exerting anti-inflammatory effects through complex actions on circulating immune cells as well as tissue-specific cells. However, long-term GC treatment causes severe side effects such as GC-induced osteoporosis due to adverse actions of GCs in mesenchymal tissues. GCs exert their effects mainly via the glucocorticoid receptor (GR) that regulates gene expression. Despite the known suppressive impact of GCs on immune cells, GC actions in the osteohematopoietic niche remain ill-defined. Thus, we aim to explore the effects of long-term GC treatment on hematopoietic stem cell (HSC) function. In preliminary investigations of GC-treated GR deficient mice, we found a reduced cell number in the bone marrow as well as a reduction of HSCs in GR-sufficient mice but not in GR-deficient mice. Furthermore, the potential of HSCs derived from bone marrow to differentiate into the various hematopoietic lineages was impaired upon long-term GC treatment. Thus, we hypothesize that long-term GC exposure affects HSC numbers, viability and function in a GR-dependent manner. Therefore, we aim to explore the effects and molecular mechanisms of GC treatment on the cellular constituents of the osteohematopoietic niche. We aim to thoroughly assess GC effects on HSC function and the cellular compartments of the niche by bone marrow transplantation studies and flow cytometric analysis. In addition, we will use genetically modified GR-mouse models to delineate the cellular targets of GCs within the bone marrow compartment utilizing immuno- and histologic investigations, gene expression analyses and ex vivo approaches. Finally we will characterize molecular pathways affected by GCs within target cells in an unbiased omics-approach on genome and protein level. Our results will provide significant insights to the molecular effects of GCs on HSCs. Dissecting the mechanisms involved could lead to the development of strategies to alleviate the deleterious effects of GCs on the osteohematopoietic niche.

• DFG Programme: Research Grants