Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide-induced oxidative stress
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Shiguang Guo1,*, Hao-Dong Fei2,*, Feng Ji2, Feng-Li Chen3, Yue Xie2 and Shou-Guo Wang2
1Department of Intensive Care Unit, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China
2Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China
3Clinical Laboratory, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China
Feng Ji, email: [email protected]
Shou-Guo Wang, email: [email protected]
Keywords: osteoblasts; oxidative stress; Nrf2; MIND4-17; Keap
Received: August 23, 2017 Accepted: October 14, 2017 Published: November 10, 2017
MIND4-17 is a recently developed NF-E2-related factor 2 (Nrf2) activator, which uniquely causes Nrf2 disassociation from Keap1. Here, we showed that pretreatment with MIND4-17 significantly inhibited hydrogen peroxide (H2O2)-induced viability reduction of primary osteoblasts and OB-6 osteoblastic cells. Meanwhile, MIND4-17 inhibited both apoptotic and non-apoptotic osteoblast cell death by H2O2. MIND4-17 treatment induced Keap1-Nrf2 disassociation, causing Nrf2 stabilization, accumulation and nuclear translocation in osteoblasts, leading to transcription of several Nrf2-dependent genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase modifier subunit (GCLM) and catalytic subunit (GCLC). Additionally, MIND4-17 largely attenuated H2O2-reactive oxygen species (ROS) production, lipid peroxidation and DNA damages. Nrf2 knockdown by targeted short hairpin RNA (shRNA) exacerbated H2O2-induced cytotoxicity in OB-6 osteoblastic cells, and nullified MIND4-17-mediated cytoprotection against H2O2. Meanwhile, Keap1 shRNA took over MIND4-17’s actions and protected OB-6 cells from H2O2. Together, MIND4-17 activates Nrf2 signaling and protects osteoblasts from H2O2.
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