Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis
Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis
复制标题
丙酮酸脱氢酶激酶 4 通过促进破骨细胞生成诱导卸载时骨质流失
DOI：
10.1016/j.bone.2011.07.012
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发表时间：
2012
期刊：
影响因子：
4.1
通讯作者：
Komori T
中科院分区：
文献类型：
--
作者：
Wang Y;Liu1 W;Masuyama R;Fukuyama R;Ito M;Zhang Q;Komori H;Murakami T;Moriishi T;Miyazaki T;Kitazawa R;Yoshida CA;Kawai Y;Izumi S;Komori T
失用性骨质疏松症常见于长期卧床休息和固定，已成为现代社会的一个主要问题；然而，卸载驱动的骨质流失的分子机制尚未完全阐明。骨细胞网络被认为是一种理想的机械传感器和机械转导系统。我们使用骨细胞网络被破坏的BCL2转基因小鼠寻找导致废用性骨质疏松症的分子。灭活丙酮酸脱氢酶复合物（PDC）的丙酮酸脱氢酶激酶4 （Pdk4）在野生型小鼠的股骨和胫骨中表达上调，而在BCL2转基因小鼠中则无上调。Pdk4−/−小鼠的骨发育正常并得到维持。然而，在卸载时，野生型小鼠由于破骨细胞生成和Rankl表达增强而骨量减少，而Pdk4−/−小鼠则没有。在M-CSF和RANKL存在下，Pdk4 - / -骨髓源性单核细胞/巨噬细胞谱系细胞（BMMs）的破骨细胞分化受到抑制，野生型BMMs和Pdk4 - / -成骨细胞共培养时，破骨细胞发生受损，其中RANKL的表达和启动子活性降低。此外，将Pdk4引入Pdk4 - / - BMMs和成骨细胞可增强破骨细胞的生成和Rankl的表达，并激活Rankl启动子。这些发现表明，Pdk4通过促进破骨细胞的发生，在卸载时骨丢失中起重要作用。
Disuse osteoporosis, which occurs commonly in prolonged bed rest and immobilization, is becoming a major problem in modern societies; however, the molecular mechanisms underlying unloading-driven bone loss have not been fully elucidated. The osteocyte network is considered to be an ideal mechanosensor and mechanotransduction system. We searched for the molecules responsible for disuse osteoporosis using BCL2 transgenic mice, in which the osteocyte network was disrupted. Pyruvate dehydrogenase kinase 4 (Pdk4), which inactivates pyruvate dehydrogenase complex (PDC), was upregulated in femurs and tibiae of wild-type mice but not of BCL2 transgenic mice after tail suspension. Bone in Pdk4−/−mice developed normally and was maintained. At unloading, however, bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild-type mice but not in Pdk4−/−mice. Osteoclast differentiation of Pdk4−/−bone marrow-derived monocyte/macrophage lineage cells (BMMs) in the presence of M-CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild-type BMMs and Pdk4−/−osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4−/−BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that Pdk4 plays an important role in bone loss at unloading by promoting osteoclastogenesis.