Low-dose dexamethasone promotes osteoblast viability by activating autophagy via the SGK1/FOXO3a signaling pathway

Area of Science:

• Bone Biology
• Cellular Mechanisms
• Autophagy Research

Background:

• Autophagy is crucial for bone homeostasis and development.
• Glucocorticoids (GCs) are known to induce autophagy, but the underlying mechanisms require elucidation.
• Understanding GC-mediated autophagy is vital for bone health research.

Purpose of the Study:

• To investigate the effect of a low dose of dexamethasone (Dex) on autophagy in mouse embryonic osteoblastic precursor cells (MC3T3-E1).
• To explore the specific molecular pathways involved in GC-induced autophagy in osteoblasts.
• To determine the role of serum- and glucocorticoid-induced kinase-1 (SGK1) in this process.

Main Methods:

• Treatment of MC3T3-E1 cells with 10^-8 M dexamethasone (Dex).
• Assessment of autophagy markers (LC3II, Beclin-1, SQSTM/p62) and cell viability/apoptosis.
• Manipulation of SGK1 expression using shRNA and investigation of the SGK1/FOXO3a pathway.
• Inhibition of autophagy using 3-methyladenine (3-MA).

Main Results:

• Low-dose Dex significantly increased SGK1 expression and activation in a time-dependent manner.
• Dex treatment promoted osteoblast viability and reduced apoptosis, effects partially mediated by autophagy.
• The SGK1/FOXO3a pathway was identified as a key mediator, with SGK1 knockdown suppressing autophagy and exacerbating cell death.
• Dex-induced autophagy markers (LC3II, Beclin-1) and inhibited SQSTM/p62 levels, which were reversed by SGK1 knockdown or 3-MA.

Conclusions:

• Low-dose glucocorticoid treatment enhances osteoblast viability by activating autophagy.
• The SGK1/FOXO3a signaling pathway is essential for mediating the autophagic response to low-dose GCs.
• This study elucidates a novel mechanism by which GCs contribute to bone homeostasis through autophagy modulation.