Activating AMP-activated protein kinase by an α1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death
Activating AMP-activated protein kinase by an α1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death
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DOI：
10.1016/j.bbrc.2016.02.036
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发表时间：
2016-03-18
影响因子：
3.1
通讯作者：
Wang, Xiao-dong
中科院分区：
文献类型：
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作者：
Guo, Shiguang;Mao, Li;Wang, Xiao-dong
糖皮质激素（GC）过量使用可导致非创伤性股骨头坏死。地塞米松（Dex）对体外培养的成骨细胞具有细胞毒作用。在这里，我们研究了化合物13（C13），一种新的α 1选择性AMP活化蛋白激酶（AMPK）激活剂，对该过程的潜在活性。我们的数据显示，C13预处理显着减弱Dex诱导的成骨细胞样MC 3 T3-E1细胞和原代小鼠成骨细胞的凋亡和坏死。AMPK活化介导成骨细胞中的C13'细胞保护作用。AMPK抑制剂化合物C、AMPK α 1的shRNA介导的敲低或AMPK α 1的显性负突变（T172 A）几乎消除了C13诱导的AMPK活化及其在成骨细胞中的促存活作用。另一方面，通过加入AMPK激活剂A-769662或外源性表达组成型活性（ca）AMPK α 1（T172 D）来强制AMPK激活，模拟C13的作用并抑制Dex诱导的成骨细胞死亡。同时，A-769662或ca-AMPK α 1几乎使C13在成骨细胞中的活性无效。进一步的研究表明，03激活AMPK依赖的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）途径，以抑制MC 3 T3-E1细胞和原代小鼠成骨细胞中Dex诱导的活性氧（ROS）产生。C13的这种作用几乎被化合物C或AMPK α 1耗尽/突变逆转。总之，这些结果表明，C13通过激活AMPK信号通路抑制Dex诱导的成骨细胞死亡。(C)2016 Elsevier Inc. All rights reserved.
Excessive glucocorticoid (GC) usage may lead to non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) exerts cytotoxic effect to cultured osteoblasts. Here, we investigated the potential activity of Compound 13 (C13), a novel alpha 1 selective AMP-activated protein kinase (AMPK) activator, against the process. Our data revealed that C13 pretreatment significantly attenuated Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. AMPK activation mediated C13' cytoprotective effect in osteoblasts. The AMPK inhibitor Compound C, shRNA-mediated knockdown of AMPK alpha 1, or dominant negative mutation of AMPK alpha 1 (T172A) almost abolished C13-induced AMPK activation and its pro-survival effect in osteoblasts. On the other hand, forced AMPK activation by adding AMPK activator A-769662 or exogenous expression a constitutively active (ca) AMPK alpha 1 (T172D) mimicked C13's actions and inhibited Dex-induced osteoblast cell death. Meanwhile, A-769662 or ca-AMPK alpha 1 almost nullified C13's activity in osteoblast. Further studies showed that 03 activated AMPK-dependent nicotinamide adenine dinucleotide phosphate (NADPH) pathway to inhibit Dex-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary murine osteoblasts. Such effects by C13 were almost reversed by Compound C or AMPK alpha 1 depletion/mutation. Together, these results suggest that C13 alleviates Dex-induced osteoblast cell death via activating AMPK signaling pathway. (C) 2016 Elsevier Inc. All rights reserved.