Activation of AMP-activated protein kinase by compound 991 protects osteoblasts from dexamethasone

作者：Xu, Yong-yi; Chen, Feng-li; Ji, Feng^*; Fei, Hao-dong; Xie, Yue; Wang, Shou-guo^*

来源：Biochemical and Biophysical Research Communications, 2018, 495(1): 1014-1021.

DOI：10.1016/j.bbrc.2017.11.132

• Dexamethasone
• Osteoblasts
• AMPK
• Oxidative stress
• Nrf2

Dexamethasone (Dex) induces direct cytotoxicity to cultured osteoblasts. The benzimidazole derivative compound 991 ("C991") is a novel and highly-efficient AMP-activated protein kinase (AMPK) activator. Here, in both MC3T3-E1 osteoblastic cells and primary murine osteoblasts, treatment with C991 activated AMPK signaling, and significantly attenuated Dex-induced apoptotic and non-apoptotic cell death. AMPK alpha 1 knockdown (by shRNA), complete knockout (by CRISPR/Cas9 method) or dominant negative mutation (T172A) not only blocked C991-mediated AMPK activation, but also abolished its pro-survival effect against Dex in osteoblasts. Further studies showed that C991 boosted nicotinamide adenine dinucleotide phosphate (NADPH) activity and induced mRNA expression of NF-E2-related factor 2-(Nrf2)-regulated genes (hem oxygenise-1 and NADPH quinone oxidoreductase 1). Additionally, C991 alleviated Dex-induced reactive oxygen species (ROS) production in osteoblasts. Notably, genetic AMPK inhibition reversed the anti-oxidant actions by C991 in Dex-treated osteoblasts. Together, we conclude that C991 activates AMPK signaling to protect osteoblasts from Dex.

• 出版日期2018-1-1
• 单位南京医科大学