AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfil-OPN axis
AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfil-OPN axis
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AMPK 通过 AMPK-Gfil-OPN 轴促进成骨并抑制脂肪生成
DOI：
10.1016/j.cellsig.2016.06.004
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发表时间：
2016-09-01
影响因子：
4.8
通讯作者：
Dai, Ke-rong
中科院分区：
文献类型：
--
作者：
Wang, Yu-gang;Qu, Xin-hua;Dai, Ke-rong
几种代谢性、遗传性和致癌性骨疾病具有骨髓基质细胞（BMSC）分化缺陷的共同病理表型。在过去几年中，骨骼科学的许多报告表明骨骼也具有内分泌作用。AMP活化蛋白激酶（AMPK）作为能量代谢传感器的作用及其如何调节BMSC分化在很大程度上是未知的。在本研究中，我们使用AMPK激动剂激活MC 3 T3-E1细胞中的AMPK，以研究AMPK在成骨中的功能作用。然而，二甲双胍和AICAR未能持续激活AMPK。因此，我们通过慢病毒载体建立了AMPK α亚基过表达的MC 3 T3-E1和3 T3-L1细胞模型，其中AMPK被过度激活。AMPK的过度激活促进MC 3 T3-E1细胞成骨，抑制3 T3-L1细胞成脂。骨桥蛋白（OPN）介导AMPK调节骨生成和脂肪生成。此外，我们提供的证据表明，转录抑制因子生长因子独立性-1（Gfil）下调，并与OPN启动子分离，以响应AMPK激活，导致OPN的上调。野生型和显性阴性Gfil的过表达调节MC 3 T3-E1骨生成和3 T3-L1脂肪生成。进一步的证据表明，AMPK通过AMPK-Gfil-OPN轴增强MC 3 T3-E1细胞的异位骨形成。总之，AMPK足以通过AMPK-Gfil-OPN轴刺激MC 3 T3-E1细胞的骨生成并抑制3 T3-L1细胞的脂肪生成。这些发现有助于阐明AMPK调控成骨和脂肪形成的分子机制。(C)2016 Elsevier Inc. All rights reserved.
Several metabolic, genetic and oncogenic bone diseases share the common pathological phenotype of defective bone marrow stromal cell (BMSC) differentiation. Many reports in bone science in the past several years have suggested that the skeleton also has an endocrine role. The role of AMP-activated protein kinase (AMPK) as an energy metabolism sensor and how it regulates BMSC differentiation is largely unknown. In the current study, we used AMPK agonists to activate AMPK in MC3T3-E1 cells to investigate the functional roles of AMPK in osteogenesis. However, metformin and AICAR failed to activate AMPK consistently. Therefore, we established MC3T3-E1 and 3T3-L1 cell models of AMPK a subunit overexpression through lentivirus vector, in which AMPK was overactivated. AMPK hyperactivation stimulated MC3T3-E1 cell osteogenesis and inhibited 3T3-L1 cell adipogenesis. Osteopontin (OPN) mediated AMPK regulation of osteogenesis and adipogenesis. Furthermore, we provided evidence that the transcriptional repressor growth factor independence-1 (Gfil) was downregulated and disassociated from the OPN promoter in response to AMPK activation, resulting in the upregulation of OPN. Overexpression of wild-type and dominant-negative Gfil modulated MC3T3-E1 osteogenesis and 3T3-L1 adipogenesis. Further evidence suggested that AMPK enhanced ectopic bone formation of MC3T3-E1 cells through the AMPK-Gfil-OPN axis. In conclusion, AMPK was sufficient to stimulate osteogenesis of MC3T3-E1 cells and inhibit adipogenesis of 3T3-L1 cells through the AMPK-Gfil-OPN axis. These findings helped elucidate the molecular mechanisms underlying AMPK regulation of osteogenesis and adipogenesis. (C) 2016 Elsevier Inc. All rights reserved.