Abaloparatide Maintains Normal Rat Blood Calcium Level in Part Via 1,25-Dihydroxyvitamin D/osteocalcin Signaling Pathway.
Abaloparatide Maintains Normal Rat Blood Calcium Level in Part Via 1,25-Dihydroxyvitamin D/osteocalcin Signaling Pathway.
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DOI：
10.1210/endocr/bqad117
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发表时间：
2023-08-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Yang, Yanmei;Tseng, Wei-Ju;Wang, Bin
甲状旁腺素相关肽（1-34）类似物abaloparatide （ABL）是治疗骨质疏松症的第二种合成代谢药物。先前的研究表明，ABL具有强大的合成代谢作用，但引起高钙血症的几率要低得多。然而，ABL维持血钙水平稳定的机制尚不清楚。我们的体内数据显示，ABL治疗（40µg/kg/天，连续7天）显著增加大鼠血液中1,25-二羟基维生素D [1,25-(OH)2D]的水平，但不升高血钙值。ABL还显著增加了血液和骨骼中由成骨细胞合成的羧化骨钙素（Gla-Ocn），并增加了因破骨细胞活化而从骨基质释放到循环系统的非羧化骨钙素。体外实验结果显示，ABL （10 nM， 24小时）对非肾细胞（大鼠成骨样细胞）1,25-(OH)2D合成和Gla-Ocn形成的直接影响不大。然而，当向细胞中添加1α-羟化酶底物25-羟基维生素D时，ABL显著促进了1,25-(OH)2D和Gla-Ocn的形成。因此，ABL处理大鼠的125 -(OH)2D水平升高导致循环中Gla-Ocn水平升高和短暂性钙升高。然后，Gla-Ocn介导骨部位细胞外液中的钙离子与骨表面的羟基磷灰石结合。Gla-Ocn的这种调节至少在一定程度上维持了ABL治疗期间血钙水平的稳定性。我们认为ABL/1,25-(OH)2D/Gla-Ocn信号通路有助于钙稳态，并可能有助于了解ABL治疗骨质疏松症的机制。
The PTH-related peptide(1-34) analog, abaloparatide (ABL), is the second anabolic drug available for the treatment of osteoporosis. Previous research demonstrated that ABL had a potent anabolic effect but caused hypercalcemia at a significantly lower rate. However, the mechanism by which ABL maintains the stability of blood calcium levels remains poorly understood. Our in vivo data showed that ABL treatment (40 µg/kg/day for 7 days) significantly increased rat blood level of 1,25-dihydroxyvitamin D [1,25-(OH)2D] without raising the blood calcium value. ABL also significantly augmented the carboxylated osteocalcin (Gla-Ocn) in the blood and bone that is synthesized by osteoblasts, and increased noncarboxylated Ocn, which is released from the bone matrix to the circulation because of osteoclast activation. The in vitro data showed that ABL (10 nM for 24 hours) had little direct effects on 1,25-(OH)2D synthesis and Gla-Ocn formation in nonrenal cells (rat osteoblast-like cells). However, ABL significantly promoted both 1,25-(OH)2D and Gla-Ocn formation when 25-hydroxyvitamin D, the substrate of 1α-hydroxylase, was added to the cells. Thus, the increased 1,25-(OH)2D levels in rats treated by ABL result in high levels of Gla-Ocn and transient calcium increase in the circulation. Gla-Ocn then mediates calcium ions in the extracellular fluid at bone sites to bind to hydroxyapatite at bone surfaces. This regulation by Gla-Ocn at least, in part, maintains the stability of blood calcium levels during ABL treatment. We conclude that the signaling pathway of ABL/1,25-(OH)2D/Gla-Ocn contributes to calcium homeostasis and may help understand the mechanism of ABL for osteoporosis therapy.
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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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