Glucocorticoid Transiently Upregulates Mitochondrial Biogenesis in the Osteoblast

Abstract

Glucocorticoid (GC)-induced bone loss is the most prevalent form of secondary osteoporosis. Previous studies demonstrated that long-term incubation of dexamethasone (DEX) induced oxidative stress and mitochondrial dysfunctions, consequently leading to apoptosis of differentiated osteoblasts. This DEX-induced cell death might be the main causes of bone loss. We previously described that DEX induced biphasic mitochondrial alternations. As GC affects mitochondrial physiology through several different possible routes, the short-term and long-term effects of GC treatment on mitochondria in the osteoblast have not been carefully characterized. Here, we examined the expression levels of genes that are associated with mitochondrial functions at several different time points after incubation with DEX. Mitochondrial biogenesis-mediated genes nuclear respiratory factor 1 (Nrf1) and Nrf2 were upregulated after 4-h incubation, and then declined after 24-h incubation, suggesting that mitochondrial biogenesis were transiently upregulated by DEX. In contrast, mitochondrial fusion gene optic atrophy 1 (Opa1) and mitofusin 2 (Mfn2) started to be elevated as the biogenesis started to decrease. Finally, the mitochondrial fission increased and apoptosis becomes prominent. Agree with the mitochondrial biphasic alterations hypothesis, the results suggested an early increase of mitochondrial activities and biogenesis upon DEX stimulation to the osteoblasts. The oxidative phosphorylation and inducible nitric oxide synthase levels increased results in oxidative stress accumulation, leading to mitochondrial fusion, and subsequently fission and triggering the apoptosis. Our results indicated that the primary effects of GC on mitochondria are promoting their functions and biogenesis. Mitochondrial breakdown and the activation of the apoptotic pathways appeared to be the secondary effect after long-term treatment.

Impact of Perioperative Dexamethasone Administration on Infection and Implant Osseointegration in a Preclinical Model of Orthopedic Device-Related Infection

“…This effect could be due to the reduction in mitochondrial activity observed in osteoclasts in the first 24 h after dexamethasone administration during an experiment carried out in vitro by a group of Taiwanese researchers [ 33 ]. In a following paper, this same group demonstrated a biphasic effect of dexamethasone on the activity of osteoblasts, with an increase in their mitochondrial activity during the first 24 h after administration [ 34 ]. This cumulative effect of decreased resorption and increased bone production, which could have occurred during the first few hours after screw implantation, could explain the increased cancellous bone density in our histopathological images.…”

Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution

“…Moreover, MAPK phosphatase-1 and annexin-1 suppress the MAPK pathway to decrease the inflammatory response [58,59]. GR binding to glucocorticoids has been shown to modulate other cellular processes that are not regulated by genomic mechanisms; for example, GRs induce changes in membrane configuration, alter MAPK signaling through the GR-binding proteins, and regulate the transcription of mitochondrial genes [60].…”