Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 2215b Garland Ave., 1155C MRBIV/ Light Hall, Nashville, TN 37232, USA.
Maine Medical Center Research Institute, 81 Research Dr., Scarborough, ME 04074, USA.
Mol Metab. 2022 Jun;60:101480. doi: 10.1016/j.molmet.2022.101480. Epub 2022 Mar 22.
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.
19 世纪末期，人们提出理论认为甲状旁腺分泌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，该蛋白（即甲状旁腺激素，PTH）的间歇性给药获得了 FDA 和 EMA 的批准，成为治疗骨质疏松症的第一种合成代谢药物。然而，关于 PTH 的骨骼作用，仍有几个悬而未决但很重要的问题尚未得到解答。
目前的研究工作集中于通过设计结构类似物和鉴定其他靶标（例如 PTH 或钙敏感受体）来提高 PTH 治疗的疗效。PTH 作用的一个独特但最近才描述的方面是其对细胞能量代谢和代谢的调节，不仅在骨骼和脂肪组织中，而且在其他组织中也是如此。本综述旨在简要介绍 PTH 先前描述的对骨骼的作用，并强调 PTH 如何调节成骨细胞的能量代谢，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来改变代谢内稳态，从而以细胞非自主的方式影响骨骼。
PTH 通过几种途径中的转录变化靶向成骨细胞来增强骨形成；最突出的途径是通过腺苷酸环化酶和 PKA。PTH 和其相关蛋白 PTHrP 也在骨细胞中诱导糖酵解和脂肪酸氧化，并在脂肪细胞中驱动脂肪分解和产热编程；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为 PTH 的时间作用提供一种新的机制。因此，PTH 的能量代谢影响可以被认为是 PTH 对骨骼的众多合成代谢作用之一。同样重要的是，从转化的角度来看，非骨骼代谢作用可能会更好地理解全身内稳态，并为治疗肌肉骨骼疾病提供新的和改进的治疗方法。
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