Osteoblast Differentiation Is Functionally Associated With Decreased AMP Kinase Activity
Osteoblast Differentiation Is Functionally Associated With Decreased AMP Kinase Activity
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DOI：
10.1002/jcp.21917
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发表时间：
2009-12-01
影响因子：
5.6
通讯作者：
Matsuguchi, Tetsuya
中科院分区：
文献类型：
--
作者：
Kasai, Takayuki;Bandow, Kenjiro;Matsuguchi, Tetsuya
成骨细胞起源于骨髓间充质干细胞，在骨形成和矿化过程中起着关键作用。一些转录因子，包括runt相关转录因子2（Runx 2）已被报道是成骨细胞分化所必需的，而细胞质信号转导通路控制的分化过程尚未完全阐明。AMP活化蛋白激酶（AMPK）是一种丝氨酸-苏氨酸激酶，通常被认为是细胞能量稳态、极性和分裂的关键调节因子。最近的证据表明，AMPK的催化α亚基的活性通过上游AMPK激酶（AMPK）（包括LKBI）的磷酸化来调节。在这里，我们探讨了AMPK在成骨细胞分化中的作用，使用体外培养模型。在成骨细胞分化过程中，AMPK α的磷酸化在原代成骨细胞和小鼠成骨细胞系MC 3 T3-E1中均显著降低。相反，原代成骨细胞和MC 3 T3-E1细胞的终末分化（以基质矿化为代表）受到葡萄糖限制和二甲双胍刺激的显著抑制，这两者都是AMPK的已知激活剂。MC 3 T3-E1细胞的基质矿化也受到AMPK α组成型活性形式的强制表达的抑制。蛋氨酸显著抑制Runx 2的基因表达，沿着成骨细胞分化标志物，包括骨钙素（Ocn）、骨唾液酸蛋白（Bsp）和骨桥蛋白（Opn）。因此，我们目前的数据表明，成骨细胞的分化与AMPK活性降低功能相关。J.细胞。221：740-749，2009。(C)2009威利-利斯公司
Osteoblasts, originating from mesenchymal stem cells, play a pivotal role in bone formation and mineralization. Several transcription factors including runt-related transcription factor 2 (Runx2) have been reported to be essential for osteoblast differentiation, whereas the cytoplasmic signal transduction pathways controlling the differentiation process have not been fully elucidated. AMP-activated protein kinase (AMPK) is a serine-threonine kinase generally regarded as a key regulator of cellular energy homeostasis, polarity, and division. Recent lines of evidence have indicated that the activity of the catalytic alpha subunit of AMPK is regulated through its phosphorylation by upstream AMPK kinases (AMPKKs) including LKBI. Here, we explored the role of AMPK in osteoblast differentiation using in vitro culture models. Phosphorylation of AMPK alpha was significantly decreased during osteoblastic differentiation in both primary osteoblasts and MC3T3-E1, a mouse osteoblastic cell line. Conversely, the terminal differentiation of primary osteoblasts and MC3T3-E1 cells, represented by matrix mineralization, was significantly inhibited by glucose restriction and stimulation with metformin, both of which are known activators of AMPK. Matrix mineralization of MC3T3-E1 cells was also inhibited by the forced expression of a constitutively active form of AMPK alpha. Metformin significantly inhibited gene expression of Runx2 along with osteoblast differentiation markers including osteocalcin (Ocn), bone sialo protein (Bsp), and osteopontin (Opn). Thus, our present data indicate that differentiation of osteoblasts is functionally associated with decreased AMPK activity. J. Cell. Physiol. 221: 740-749, 2009. (C) 2009 Wiley-Liss, Inc.