Primary Osteocyte Supernatants Metabolomic Profiling of Two Transgenic Mice With Connexin43 Dominant Negative Mutants.
Primary Osteocyte Supernatants Metabolomic Profiling of Two Transgenic Mice With Connexin43 Dominant Negative Mutants.
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两种带有 Connexin43 显性阴性突变体的转基因小鼠的原代骨细胞上清液代谢组学分析
DOI：
10.3389/fendo.2021.649994
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发表时间：
2021
影响因子：
5.2
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Chen M;Li G;Zhang L;Ning K;Yang B;Jiang JX;Wang DE;Xu H
骨细胞可通过缝隙连接和半通道向细胞外环境释放前列腺素E2（PGE 2）、一氧化氮（NO）和三磷酸腺苷（ATP）等小分子物质（≤ 1 kDa），这些物质在骨细胞与其他组织细胞之间的信号传递中起重要作用。连接蛋白43（Cx 43）是骨细胞中最丰富的连接蛋白。为了进一步发现骨细胞通过Cx43通道释放的分子，更好地理解Cx43通道在骨细胞中的调节功能，我们使用液相色谱-串联质谱法进行了非靶向全局代谢组学分析（LC-MS/MS）对从两种转基因小鼠模型分离的骨细胞收集的条件培养基进行分析，所述转基因小鼠模型具有由10 kb-DMP 1启动子驱动的Cx43显性失活突变体：R76 W（间隙连接被阻断，而半通道被促进）和Δ130-136（间隙连接和半通道都被阻断）。结果表明，几个新的类别的分子，如“脂肪酰基”和“羧酸及其衍生物”，可以通过骨细胞Cx43通道释放。此外，Cx43通道功能的改变影响与炎症反应和氧化应激相关的代谢产物的释放。途径分析进一步表明柠檬酸循环是Cx43通道调控的最具差异性的代谢途径。总之，这些结果分离了骨细胞通过Cx43通道释放的新的潜在代谢产物，为理解骨细胞对自身和其他细胞的调控机制提供了新的视角。
Osteocytes could release some small molecules (≤ 1 kDa) through gap junctions and hemichannels to extracellular environment, such as prostaglandin E2 (PGE2), nitric oxide (NO) and adenosine triphosphate (ATP), which play key roles in transferring signals between bone cells and other tissue cells. Connexin (Cx) 43 is the most abundant connexin in osteocytes. To further discover molecules released by osteocytes through Cx43 channels and better understand the regulatory function of Cx43 channels in osteocytes, we performed non-targeted global metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on conditioned medium collected from osteocytes isolated from two transgenic mouse models with Cx43 dominant negative mutants driven by a 10 kb-DMP1 promoter: R76W (gap junctions are blocked, whereas hemichannels are promoted) and Δ130-136 (both gap junctions and hemichannels are blocked). The results revealed that several new categories of molecules, such as “fatty acyls” and “carboxylic acids and derivatives”, could be released through osteocytic Cx43 channels. In addition, alteration of Cx43 channel function affected the release of metabolites related to inflammatory reaction and oxidative stress. Pathway analysis further showed that citric acid cycle was the most differential metabolic pathway regulated by Cx43 channels. In sum, these results isolated new potential metabolites released by osteocytes through Cx43 channels, and offered a novel perspective to understand the regulatory mechanisms of osteocytes on themselves and other cells as well.
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影响因子：
16.2
作者：
Brignardello, Enrico;Runzo, Cristina;Boccuzzi, Giuseppe
通讯作者：
Boccuzzi, Giuseppe
影响因子：
4
作者：
Li, GuoBin;Zhang, Lan;Shang, Peng
通讯作者：
Shang, Peng
影响因子：
4
作者：
Brignardello, E;Beltramo, E;Boccuzzi, G
通讯作者：
Boccuzzi, G
影响因子：
3.3
作者：
Cherian, PP;Siller-Jackson, AJ;Jiang, JX
通讯作者：
Jiang, JX
影响因子：
4.8
作者：
Bacabac, Rommel G.;Smit, Theo H.;Klein-Nulend, Jenneke
通讯作者：
Klein-Nulend, Jenneke