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

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

  • Eur J Pharmacol. 2022 Apr 15;921:174871. doi: 10.1016/j.ejphar.2022.174871.
Xiaohui Liu 1 Yating Sun 2 Qilu Wei 1 Wuqiang Jiang 3 Ming Jiao 1 Junteng Yan 1 Run Tian 1 Pei Yang 4 Kunzheng Wang 5 Chunsheng Wang 6
Affiliations

Affiliations

  • 1 Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Department of Orthopaedic Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an, China.
  • 4 Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: yangpei@xjtu.edu.cn.
  • 5 Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: wkzh1955@163.com.
  • 6 Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: wcs420@163.com.
Abstract

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.

Keywords

Angiotensin-(1-7); Apoptosis; Captopril; Glucocorticoid; Mas receptor; Osteonecrosis of the femoral head.

Figures
Products