Abstract
Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.
Highlights
Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm
This review summarizes the status of current studies on cellular and molecular, endogenous and exogenous GC actions via the GC receptor (GR) in bone cells
When GC signaling was disrupted in osteoblasts using Col2.3-11ß-HSD2 mice [76], intramembranous bone formation was not affected, whereas GR deletion in chondroblasts using GRCol2CreERT2 mice resulted in impaired endochondral bone healing, by increasing the cartilaginous fraction of the fracture callus [77]
Summary
Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Endogenous GCs directly regulate bone homeostasis via the GR in a cell-type specific manner. Osteoclasts, another key cell type for bone mass regulation, are not affected by endogenous GC signaling.
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