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AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfil-OPN axis

机译：AMPK通过AMPK-Gfil-OPN轴促进成骨并抑制脂肪生成

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摘要

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.
机译：几种代谢性，遗传性和致癌性骨疾病具有缺陷的骨髓基质细胞（BMSC）分化的常见病理表型。过去几年中，骨骼科学方面的许多报道表明，骨骼也具有内分泌作用。 AMP激活的蛋白激酶（AMPK）作为能量代谢传感器的作用及其如何调节BMSC分化在很大程度上尚不清楚。在当前的研究中，我们使用了AMPK激动剂来激活MC3T3-E1细胞中的AMPK，以研究AMPK在成骨中的功能。但是，二甲双胍和AICAR无法持续激活AMPK。因此，我们建立了AMPK的MC3T3-E1和3T3-L1细胞模型，其中AMPK是通过慢病毒载体过度表达的亚基，其中AMPK被过度激活。 AMPK过度激活刺激MC3T3-E1细胞成骨并抑制3T3-L1细胞成脂。骨桥蛋白（OPN）介导AMPK调节成骨和脂肪形成。此外，我们提供的证据表明，转录阻遏物生长因子独立性1（Gfil）被下调并响应AMPK激活而与OPN启动子解除关联，从而导致OPN上调。野生型和显性负Gfil的过度表达调节MC3T3-E1成骨和3T3-L1脂肪形成。进一步的证据表明，AMPK通过AMPK-Gfil-OPN轴增强了MC3T3-E1细胞的异位骨形成。总之，AMPK足以刺激MC3T3-E1细胞成骨并通过AMPK-Gfil-OPN轴抑制3T3-L1细胞的脂肪形成。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.保留所有权利。

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