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A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunolog

Ahmad M1Hachemi Y1Paxian K1Mengele F1,2Koenen M1,3Tuckermann J1.

Front Immunol. 2019 Oct 17;10:2460. doi: 10.3389/fimmu.2019.02460. eCollection 2019.

 

Abstract

Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging.

OVERALL CONCLUSION/OUTLOOK

Overall GCs and the GR have complex actions in bone diseases. The power of conditional mouse genetics demonstrated that GC signaling and GR action in distinct cell types of the immune system, stromal cells and bone cells have different contributions to the overall effects of GCs. Moreover, going away from this simplistic approach of interpreting cell type specific—cell autonomous effects, the field is now moving toward understanding the impact of GCs on interactions of distinct cell types or even organs. Other issues that remain unexplored are the interplay of GC triggered immune cells in the normal pathology of postmenopausal and age-related osteoporosis. This is striking since the immune cells from the bone marrow need the bone as a niche, therefore strong interactions of immune and bone cells occur as a normal physiological process. Given that GCs are part of the neuroendocrine regulatory network that also control inflammation and healthy bone homeostasis, a more holistic view will be needed. With the technologies of high content analysis, single cell sequencing and systemic approaches in combination with organoid models and carefully interpreted animal models, our understanding will substantially increase about the influence of these versatile hormones on the immune-metabolic crosstalk