Anabolic actions of PTH in murine models: two decades of insights.
Anabolic actions of PTH in murine models: two decades of insights.
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DOI：
10.1002/jbmr.4389
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
McCauley LK
中科院分区：
文献类型：
--
作者：
Zweifler LE;Koh AJ;Daignault-Newton S;McCauley LK
甲状旁腺激素 (PTH) 是甲状旁腺响应低血清钙浓度而产生的，其目标是骨骼、肾脏，并间接影响肠道。 PTH 的 N 末端因其间歇性给药 (iPTH) 刺激骨形成的能力而被研究了数十年，并在临床上用作治疗骨质疏松症的有效合成代谢剂。尽管人们对 iPTH 及其临床应用很感兴趣，但 PTH 的作用机制仍然很复杂且尚未完全确定。 90 多个小鼠模型中的 70 多个基因靶标已被用来更好地了解 PTH 合成代谢作用。由于小鼠研究使用野生型小鼠作为阳性对照，因此对各种变量进行了分析，以更好地了解 iPTH 发挥作用的最佳条件。对 iPTH 的反应最大的是雄性小鼠，治疗开始时间晚于 12 周龄，治疗持续时间持续 5-6 周，PTH 剂量为 30-60μg/kg/天。这项综合研究还评估了这些与骨形成作用相关的遗传模型，主要关注小梁室，揭示与 PTH 合成代谢作用相关的关键基因和基因家族的趋势。这些数据的总和揭示了 iPTH 导致小梁骨体积增加最大的基因缺失。其中包括 PTH 和 1-α-羟化酶（Pth;1α(OH)ase，62 倍）、双调蛋白（Areg，15.8 倍）和 PTH 相关蛋白（Pthrp，10.2 倍）。对合成代谢反应抑制最大的缺失包括：蛋白聚糖4（Prg4，-9.7倍）、低密度脂蛋白受体相关蛋白6（Lrp6，1.3倍）和低密度脂蛋白受体相关蛋白5（Lrp5，-1.0倍）的缺失。 iPTH 的合成代谢作用受到多种不同基因的广泛影响。这些数据为未来的研究和开发以及人类治疗的应用提供了重要的见解。 © 2021 作者。 《Journal of Bone and Mineral Research》由 Wiley periodicals LLC 代表美国骨与矿物研究学会 (ASBMR) 出版。
Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N‐terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild‐type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5–6 weeks, and a PTH dose of 30–60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1‐α‐hydroxylase (Pth;1α(OH)ase, 62‐fold), amphiregulin (Areg, 15.8‐fold), and PTH related protein (Pthrp, 10.2‐fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, −9.7‐fold), low‐density lipoprotein receptor‐related protein 6 (Lrp6, 1.3‐fold), and low‐density lipoprotein receptor‐related protein 5 (Lrp5, −1.0‐fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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