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

内分泌学 内科学 化学 糖皮质激素受体 骨保护素 盐皮质激素受体 兰克尔 血管紧张素II 受体 糖皮质激素 生物 医学 激活剂(遗传学)
作者
Xiaohui Liu,Yating Sun,Qilu Wei,Wuqiang Jiang,Ming Jiao,Junteng Yan,Run Tian,Pei Yang,Kunzheng Wang,Chunsheng Wang
出处
期刊:European Journal of Pharmacology [Elsevier]
卷期号:921: 174871-174871 被引量:3
标识
DOI:10.1016/j.ejphar.2022.174871
摘要

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.
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