Paeonol regulates autophagy through the PI3K-AKT-mTOR signaling pathway to inhibit apoptosis of osteocytes

Osteoporosis is the most common complication of glucocorticoids and predisposes to fractures. Excessive Apoptosis of osteocytes is the pathological feature of glucocorticoid-induced osteoporosis. Paeonol, an effective component of Traditional Chinese Medicine Cortex Moutan, known for its anti-inflammatory and analgesic properties, has a long clinical application history. However, the regulatory effect of paeonol on the fate of osteocytes under excessive glucocorticoid remains unclear. The present study aimed to investigate the effect of paeonol against osteocyte death and osteoporosis induced by glucocorticoid and to explore the underlying mechanisms. We found that paeonol not only improved the low proliferation rate of osteocytes induced by dexamethasone but also weakened the dexamethasone-induced Apoptosis of osteocytes by stimulating cytoprotective Autophagy. Subsequently, proteomic Sequencing identified the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) - protein kinase B (Akt) signaling pathway as the potential target of paeonol in attenuating dexamethasone-induced osteocyte injury, and the PI3K Activator and inhibitor confirmed this hypothesis. In vivo, paeonol alleviated glucocorticoid-induced osteoporosis, promoted Autophagy and inhibited Apoptosis of osteocytes by regulating PI3K phosphorylation. In brief, paeonol protects osteocytes from dexamethasone-derived Apoptosis by increasing protective Autophagy, further inhibiting osteoporosis. Its autophagy-promoting effect was associated with inhibition of PI3K-AKT-mechanistic target of rapamycin (mTOR) of osteocytes.

Apoptosis; Autophagy; Glucocorticoid; MLO-Y4 osteocytes; PI3K/Akt/mTOR pathway; Paeonol.