Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks.
Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks.
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DOI：
10.1016/j.molmet.2022.101480
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发表时间：
2022-06
影响因子：
8.1
通讯作者：
Rosen CJ
中科院分区：
文献类型：
--
作者：
Rendina-Ruedy E;Rosen CJ
19世纪晚期，有一种理论认为甲状旁腺产生的一种循环产物可能会对骨骼内稳态产生负面影响。一个世纪后，这种蛋白质（即甲状旁腺激素，PTH）间歇性给药被美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准为第一种治疗骨质疏松症的合成代谢药物。然而，关于PTH对骨骼的作用仍有几个重要问题尚未得到解答。
目前的研究工作集中在通过设计结构类似物和确定其他靶点（例如，PTH或钙敏感受体）来提高PTH治疗的疗效。PTH作用的一个独特但直到最近才被描述的方面是它对细胞生物能量学和代谢的调节，不仅在骨骼和脂肪组织中，也在其他组织中。本篇综述旨在简要介绍PTH之前被描述的对骨骼的作用，并强调PTH如何调节成骨细胞的生物能量学，从而促进更多的骨形成。它还将阐明PTH如何通过其在其他细胞和组织中的作用改变代谢内稳态，从而以一种非细胞自主的方式影响骨骼。
PTH给药通过在几个通路中引起转录变化作用于成骨细胞从而促进骨形成；最显著的是通过腺苷酸环化酶和蛋白激酶A（PKA）。PTH及其相关蛋白，甲状旁腺激素相关蛋白（PTHrP），也能诱导骨细胞中的糖酵解和脂肪酸氧化，并驱动脂肪细胞中的脂解和产热程序；后者可能间接但积极地影响骨骼代谢。虽然还有很多工作要做，但细胞代谢的改变也可能提供一种与PTH的时间作用相关的新机制。因此，PTH的生物能量学影响可被视为PTH对骨骼的无数合成代谢作用中的另一种。同样从转化的角度来看很重要的是，非骨骼代谢效应可能会使人们更好地理解全身内稳态，以及带来新的和改进的治疗肌肉骨骼疾病的方法。
Late in the nineteenth century, it was theorized that a circulating product produced by the parathyroid glands could negatively impact skeletal homeostasis. A century later, intermittent administration of that protein, namely parathyroid hormone (PTH), was approved by the FDA and EMA as the first anabolic agent to treat osteoporosis. Yet, several unanswered but important questions remain about the skeletal actions of PTH. Current research efforts have focused on improving the efficacy of PTH treatment by designing structural analogs and identifying other targets (e.g., the PTH or the calcium sensing receptor). A unique but only recently described aspect of PTH action is its regulation of cellular bioenergetics and metabolism, namely in bone and adipose tissue but also in other tissues. The current review aims to provide a brief background on PTH's previously described actions on bone and highlights how PTH regulates osteoblast bioenergetics, contributing to greater bone formation. It will also shed light on how PTH could alter metabolic homeostasis through its actions in other cells and tissues, thereby impacting the skeleton in a cell non-autonomous manner. PTH administration enhances bone formation by targeting the osteoblast through transcriptional changes in several pathways; the most prominent is via adenyl cyclase and PKA. PTH and its related protein, PTHrP, also induce glycolysis and fatty acid oxidation in bone cells and drive lipolysis and thermogenic programming in adipocytes; the latter may indirectly but positively influence skeletal metabolism. While much work remains, alterations in cellular metabolism may also provide a novel mechanism related to PTH's temporal actions. Thus, the bioenergetic impact of PTH can be considered another of the myriad anabolic effects of PTH on the skeleton. Just as importantly from a translational perspective, the non-skeletal metabolic effects may lead to a better understanding of whole-body homeostasis along with new and improved therapies to treat musculoskeletal conditions.
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影响因子：
13.6
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
5.6
作者：
Sabbieti, Maria Giovanna;Agas, Dimitrios;Xiao, Liping;Marchetti, Luigi;Coffin, J. Douglas;Doetschman, Thomas;Hurley, Marja M.
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通讯作者：
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