Alpha-2-macroglobulin attenuates glucocorticoid-induced osteonecrosis of the femoral head by enhancing osteogenesis and antioxidant defense via the Akt/Nrf2 signaling pathway.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is featured by oxidative stress and impaired bone regeneration. Alpha-2-Macroglobulin (α-2 M) was reported to possess cytoprotective and anti-inflammatory properties, and have shown its role in alleviating GIONFH. nuclear factor erythroid 2-related factor 2 (Nrf2) was proved to mediate oxidative stress in GIONFH. We aimed to investigate whether α-2 M attenuates GIONFH by exerting a dual osteogenic and antioxidant effect through the Akt/Nrf2 signaling pathway. We induced GIONFH model in rats and injected α-2 M and Nrf2 inhibitor subsequently. Micro-CT and histology revealed that α-2 M treatment prevented methylprednisolone (MPS)-induced bone loss, preserving trabecular structure and reducing empty lacunae. α-2 M reversed the MPS-mediated suppression of Akt-Nrf2 pathway, upregulating the expression of heme oxygenase-1 (HO-1) and osteogenic markers. The Nrf2 inhibitor ML385 negated these benefits, confirming that α-2 M mitigates GIONFH by upregulating osteogenesis and reducing oxidative stress through the Akt/Nrf2 axis. The results demonstrated that α-2 M is a promising target for managing GIONFH.