Captopril alleviates glucocorticoid-induced osteonecrosis of the femoral head by mediating the ACE2/ Ang-(1-7)/Mas receptor cascade.

The renin–angiotensin–aldosterone system (RAAS) is locally expressed in skeletal tissue and is known to affect bone health. This study investigated the therapeutic effects and potential mechanisms of the angiotensin-converting enzyme inhibitor (ACEI) captopril (CAP) in a rat model of glucocorticoid-induced femoral head necrosis (GIONFH). Bone marrow mesenchymal stem cells (mBMSC) from mice treated with dexamethasone (DEX) in vitro and methylprednisolone (MPS)-induced rats in vivo were used to explore the effects and mechanisms of CAP, respectively. Cell proliferation was detected in vitro by the CCK-8 assay, apoptosis by Annexin V-FITC-PI and Western blotting, and reactive oxygen species (ROS) by the DCFH-DA probe. Osteogenic ability was assessed by alkaline phosphatase and alizarin red staining. In vivo hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling, immunohistochemistry, enzyme-linked immunosorbent assay, micro-computed tomography, RT-PCR, and Western blotting were also performed. The in vitro data showed that CAP promotes DEX-induced mBMSC proliferation, reduces apoptosis and ROS accumulation, and promotes osteogenesis. However, these protective effects were partially counteracted by A-779, a specific Mas-receptor antagonist. In vivo experiments showed that CAP prevented MPS-induced osteonecrosis, attenuated inflammation levels, and corrected bone metabolism and bone loss while reversing MPS-induced upregulation of ACE1, AT1-receptor, and RANKL expression and downregulation of ACE2, Mas-receptor, and osteoprotegerin expression. Taken together, these findings demonstrate for the first time that CAP exerts anti-inflammatory, antioxidant, anti-apoptotic, and osteoprotective effects against GIONFH by activating the ACE2/Ang-(1-7)/Mas receptor signaling pathway, which expands a new strategy for the treatment of orthopedic diseases. [ABSTRACT FROM AUTHOR]