A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.
A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.
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DOI：
10.1073/pnas.2212178119
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发表时间：
2022-11-08
影响因子：
11.1
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中科院分区：
文献类型：
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在本文中，我们描述了一个代谢途径，解释了为什么以及如何在矿化组织中储存大部分身体的柠檬酸盐的长期困惑。其机制涉及柠檬酸膜转运体SLC13A5与柠檬酸通过三羧酸循环内源性产生和输出之间的协调作用。在小鼠中，这种途径的功能丧失会降低骨量和强度，并破坏牙齿的矿化，这一表型特征与SLC13A5突变儿童的表型特征相同。这些发现表明，骨成骨细胞和牙齿成釉细胞/成牙细胞作为专门的柠檬酸盐产生细胞，确保柠檬酸盐沉积成矿物质，这是骨骼和牙齿正常形成所必需的。柠檬酸盐是哺乳动物细胞中重要的代谢底物和能量代谢的关键调节剂。几十年来，人们都知道骨骼含有人体大部分的柠檬酸盐（约85%），但是这种代谢物为什么以及如何在骨骼中分配的问题却很少受到关注。在这里，我们发现成骨细胞使用一种特殊的代谢途径来调节柠檬酸盐的摄取、内源性生产和沉积到骨骼中。成骨细胞高水平表达膜性Na+依赖性柠檬酸转运体溶质载体家族13成员5 （Slc13a5）基因。抑制或遗传破坏Slc13a5减少成骨柠檬酸盐摄取和破坏矿物结节形成。缺乏Slc13a5或在成骨细胞中选择性缺乏Slc13a5的小鼠的骨骼显示出相同的皮质厚度减少，机械强度也同样受损。令人惊讶的是，来自Slc13a5 - / -成骨细胞的矿物质中柠檬酸盐含量相对于对照增加了四倍，这表明代偿机制参与了内源性柠檬酸盐的产生。事实上，通过顶膜柠檬酸转运蛋白SLC13A5和线粒体锌转运蛋白（ZIP1；由Slc39a1编码）的协同作用，SLC13A5介导柠檬酸从血液中进入，其活性对细胞质柠檬酸进行稳态控制。锌转运蛋白是三羧酸循环中柠檬酸外排的介质。有趣的是，SLC13A5缺陷小鼠也表现出牙釉质和牙本质形成缺陷，这是一种临床特征，我们发现这在SLC13A5突变儿童的乳牙中也有重现。总之，我们的研究结果揭示了成骨细胞代谢途径的组成部分，该途径通过调节柠檬酸盐沉积成矿物羟基磷灰石来影响骨强度。
In this paper, we describe a metabolic pathway that explains the long-standing puzzle as to why and how the majority of the body’s citrate is stored in mineralized tissues. The mechanism involves the coordinated actions between the membranous citrate transporter SLC13A5 and the endogenous production and export of citrate through the tricarboxylic acid cycle. Loss of function of this pathway in mice decreased bone mass and strength and disrupted the mineralization of teeth, a phenotypic feature identical to that seen in children with mutations in SLC13A5. These findings demonstrate that bone osteoblasts and tooth ameloblasts/odontoblasts function as specialized citrate-producing cells to ensure the deposition of citrate into mineral, where it is required for the proper formation of bones and teeth. Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body’s citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na+-dependent citrate transporter solute carrier family 13 member 5 (Slc13a5) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a5−/− osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5-deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.
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DOI：
10.3390/molecules22030378
发表时间：
2017-02-28
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bhutia YD;Kopel JJ;Lawrence JJ;Neugebauer V;Ganapathy V
通讯作者：
Ganapathy V
影响因子：
3.7
作者：
Irizarry AR;Yan G;Zeng Q;Lucchesi J;Hamang MJ;Ma YL;Rong JX
通讯作者：
Rong JX
DOI：
10.18689/mjdl-1000120
发表时间：
2018-01-01
期刊：
Madridge journal of dentistry and oral surgery
影响因子：
--
作者：
Costello, L C;Franklin, R B;Reynolds, M A
通讯作者：
Reynolds, M A
DOI：
10.1016/0065-2571(75)90029-1
发表时间：
1975-01-01
期刊：
Advances in enzyme regulation
影响因子：
--
作者：
Halperin, M L;Cheema-Dhadli, S;Fritz, I B
通讯作者：
Fritz, I B
影响因子：
4.8
作者：
Inoue, K;Zhuang, L;Ganapathy, V
通讯作者：
Ganapathy, V