Parathyroid Hormone Reprograms Osteoblast Metabolism.
Parathyroid Hormone Reprograms Osteoblast Metabolism.
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DOI：
10.1002/jbmr.2727
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发表时间：
2015-11
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通讯作者：
Riddle RC
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作者：
Riddle RC
地球生命进化中的一个重要事件是真核生物的出现，真核生物获得了分隔的细胞内结构，使其代谢过程能够高效、灵活地产生能量。当三羧酸 (TCA) 循环和氧化磷酸化完全参与并且糖酵解中产生的丙酮酸被分流至线粒体氧化为 CO2 时，单分子葡萄糖可用于促进 36 分子 ATP 的合成，用于细胞过程。然而，在某些情况下，细胞会放弃这种能量输送，并将其代谢程序转换为更快速但效率较低的 ATP 生产模式，称为有氧糖酵解或 Warburg 效应。在此过程中，一分子葡萄糖在糖酵解中产生 2 个 ATP，所得丙酮酸转化为乳酸或穿梭至其他生物合成途径。临床上用于识别快速分裂的恶性细胞的高葡萄糖消耗率需要维持细胞 ATP 水平。(1, 2) 50 多年前进行的研究表明，干骺端骨切片中存在的骨细胞以及随后分离的颅骨成骨细胞培养物使用葡萄糖进行高度糖酵解，其速率几乎相当于肝细胞，但耗氧率低得多。(3-5) 有人提出，成骨细胞消耗的葡萄糖中有 80% 转化为乳酸它与葡萄糖代谢中的另一种中间体柠檬酸盐一起，将促进骨转换过程，并有助于矿物质离子在细胞外环境中的总体溶解度。(3, 6-8) 尽管最近的研究表明不完全葡萄糖代谢的产物会影响骨生物矿化，但这一将成骨细胞生物能学和骨功能联系起来的有趣想法在很大程度上被该领域所遗忘。(9, 10)在过去的十五年里，人们对骨细胞的代谢需求重新产生了兴趣受到两个相关角度的研究的推动。首先，从细胞生物学的角度来看，细胞增殖和分化的能量消耗已经得到了更大的重视。特别是，蛋白质合成是成骨细胞在制备和沉积丰富的细胞外基质时的主要功能，也是能量消耗最高的细胞过程之一。(11, 12)
Aseminal event in the evolution of life on Earth was the emergence of the eukaryotes, which acquired compartmentalized intracellular structures that enabled their metabolic processes to produce energy with great efficiency and flexibility. When the tricarboxylic acid (TCA) cycle and oxidative phosphorylation are fully engaged and pyruvate generated in glycolysis is shunted to the mitochondria for oxidation to CO2, a single molecule of glucose can be utilized to fuel the synthesis of 36 molecules of ATP for use in cellular processes. In some instances, however, cells forego this energetic-haul and switch their metabolic program to a more rapid but less efficient mode of ATP production known as aerobic glycolysis or the Warburg effect. In this process, one molecule of glucose is used to generate 2 ATP in glycolysis and the resulting pyruvate is converted to lactate or shuttled to other biosynthetic pathways. A high rate of glucose consumption, which is used clinically to identify rapidly dividing malignant cells, is then required to maintain cellular ATP levels.(1, 2) Studies conducted more than 50 years ago demonstrated that bone cells present in metaphyseal bone slices and then isolated calvarial osteoblast cultures are highly glycolytic using glucose at a rate nearly equivalent to hepatocytes but at much lower rates of oxygen consumption.(3-5) It was proposed that 80% of the glucose consumed by osteoblasts was converted to lactate and this together with citrate, another intermediate in the metabolism of glucose, would facilitate the process of bone turnover and also contribute to the overall solubility of mineral ions in the extracellular milieu.(3, 6-8) This intriguing idea linking osteoblast bioenergetics and bone function was largely forgotten by the field despite more recent work suggesting that products of incomplete glucose metabolism impact bone biomineralization.(9, 10)Over the last decade and a half, a renewed interest in the metabolic requirements of bone cells has been motivated by studies from two related perspectives. First, from a cellular biology perspective, the energetic costs of cellular proliferation and differentiation have gained greater appreciation. In particular, protein synthesis, a major function of osteoblasts as they prepare and deposit an abundant extracellular matrix, is among the most energetically costly cellular process.(11, 12) The