Alpha-2-macroglobulin mitigates glucocorticoid-induced osteonecrosis via Keap1/Nrf2 pathway activation

Area of Science:

• Biochemistry
• Cell Biology
• Medical Research

Background:

• Glucocorticoids (GCs) are commonly prescribed but can cause osteonecrosis of the femoral head (ONFH).
• Alpha-2-macroglobulin (A2M) influences oxidative stress and biological processes, but its role in GCs-induced ONFH is unclear.
• Understanding A2M's function in ONFH is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of Alpha-2-macroglobulin (A2M) in glucocorticoid-induced osteonecrosis of the femoral head (ONFH).
• To examine the activation of the Keap1/Nrf2 signaling pathway by A2M in the context of ONFH.
• To explore A2M as a potential therapeutic target for GCs-induced ONFH.

Main Methods:

• Transcriptomic and proteomic analyses of patient samples with GCs-induced ONFH.
• Development of a rat model for GCs-induced ONFH with A2M overexpression.
• Histopathological staining, single-cell RNA sequencing, and proteomic analysis.
• In vivo and in vitro experiments to assess the effects of A2M on oxidative stress and apoptosis.

Main Results:

• A significant downregulation of A2M was observed in patients with GCs-induced ONFH.
• A2M overexpression in a rat model promoted anti-inflammatory macrophage proliferation.
• A2M significantly alleviated ONFH symptoms by reducing oxidative stress and apoptosis.
• The Keap1/Nrf2 signaling pathway was identified as a key mediator of A2M's protective effects.

Conclusions:

• Alpha-2-macroglobulin (A2M) plays a critical protective role in mitigating glucocorticoid-induced osteonecrosis of the femoral head (ONFH).
• A2M functions by modulating oxidative stress and apoptosis through the Keap1/Nrf2 pathway.
• These findings highlight A2M as a promising therapeutic target for GCs-induced ONFH.