Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis.
Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis.
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AMPK α1 和 α2 亚基在成骨、成骨细胞相关的破骨细胞生成和脂肪生成中的功能差异
DOI：
10.1038/srep32771
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发表时间：
2016-09-07
影响因子：
4.6
通讯作者：
Tang TT
中科院分区：
文献类型：
--
作者：
Wang YG;Han XG;Yang Y;Qiao H;Dai KR;Fan QM;Tang TT
在骨质疏松症、肥胖症和糖尿病等人类疾病中受损的内分泌作用在以前已经得到了强调。在这些疾病中，AMPK作为能量代谢的传感器和调节器的作用具有生物学和临床重要性。由于AMPK的主要催化亚基α有两种异构体，目前还不清楚它们之间是否存在骨骼系统的功能差异。本研究通过慢病毒转导在MC 3 T3-E1细胞、原代成骨细胞和小鼠BMSCs中过表达AMPKα1和α2。过表达AMPKα2的细胞具有比AMPKα1更高的成骨潜能，其中雄激素受体（AR）和骨激活素起重要作用。RANKL和M-CSF从过度表达α2的细胞中分泌的水平低于α1，导致成骨细胞相关破骨细胞生成减少。在3 T3-L1细胞中，过表达α2的细胞比过表达α1的细胞对脂肪生成的抑制程度更大，这是由AR调节的。AMPKα2在纤维结构不良（FD）表型的人BMSCs中异常下调。AMPKα2在这些细胞中的过表达挽救了成骨缺陷，表明AMPKα2在FD发病机制中起作用。这些发现突出了AMPKα1和α2之间的功能差异，并为研究与骨骼系统功能受损相关的疾病的分子机制提供了基础。
The endocrine role of the skeleton-which is impaired in human diseases including osteoporosis, obesity and diabetes-has been highlighted previously. In these diseases, the role of AMPK, a sensor and regulator of energy metabolism, is of biological and clinical importance. Since AMPK’s main catalytic subunit α has two isoforms, it is unclear whether functional differences between them exist in the skeletal system. The current study overexpressed AMPKα1 and α2 in MC3T3-E1 cells, primary osteoblasts and mouse BMSCs by lentiviral transduction. Cells overexpressing AMPKα2 showed higher osteogenesis potential than AMPKα1, wherein androgen receptor (AR) and osteoactivin played important roles. RANKL and M-CSF were secreted at lower levels from cells overexpressing α2 than α1, resulting in decreased osteoblast-associated osteoclastogenesis. Adipogenesis was inhibited to a greater degree in 3T3-L1 cells overexpressing α2 than α1, which was modulated by AR. An abnormal downregulation of AMPKα2 was observed in human BMSCs exhibiting the fibrous dysplasia (FD) phenotype. Overexpression of AMPKα2 in these cells rescued the defect in osteogenesis, suggesting that AMPKα2 plays a role in FD pathogenesis. These findings highlight functional differences between AMPKα1 and α2, and provide a basis for investigating the molecular mechanisms of diseases associated with impaired functioning of the skeletal system.
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