Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

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.

Zuo-Gui-Wan Aqueous Extract Ameliorates Glucocorticoid-Induced Spinal Osteoporosis of Rats by Regulating let-7f and Autophagy

“…The main pathological cause of GIOP is an imbalance of bone homeostasis between osteoblastic bone formation and osteoclastic bone resorption ( 23 ). Previous studies indicated that GCs resulted in bone impairment by reducing osteoblast differentiation, promoting the apoptosis of osteoblasts and osteocytes, and prolonging the life span of osteoclasts ( 2 , 23 ). Furthermore, GCs can affect bone metabolism by regulating canonical Wnt-β-catenin and OPG/RANKL/RANK signaling, respectively ( 24 ).…”

Denosumab Can Prevent Collapse in Patients with Early‐Stage Steroid‐Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy

“…Namely, in this study, all included cases of ONFH were steroid induced. It has already been well established that glucocorticoids directly affect bone metabolism, greatly enhancing osteoclastic bone resorption and inhibiting osteogenesis 15,16 . As a monoclonal antibody against receptor‐activator of nuclear factor κ‐B ligand (RANKL), denosumab could promote the apoptosis of osteoclasts and inhibit the bone resorption induced by osteoclasts, 17,18 which might be the predominant reason for femoral head collapse in patients with steroid ONFH 18 .…”

Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System

“…Obviously, the use of some medications to treat co-morbidities could also influence outcomes depending on the type and dosages being used. Treatment with anti-inflammatory medications, such as NSAIDS [ 67 , 68 , 69 ] or high or continuous doses of glucocorticoids [ 70 , 71 ], could potentially adversely affect outcomes after interventions with cell therapy approaches. Therefore, the presence of co-morbidities and their treatment, as well age and sex, should be recognized and addressed before initiating interventions to enhance the repair/regeneration of injured connective tissues of the MSK system.…”