The Center for Translational Medicine, Departments of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Endocrinology. 2023 Aug 1;164(9). doi: 10.1210/endocr/bqad117.
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.
甲状旁腺激素相关肽（1-34）类似物，阿巴洛肽（ABL），是第二种可用于治疗骨质疏松症的合成代谢药物。先前的研究表明，ABL 具有很强的合成代谢作用，但导致高钙血症的发生率明显较低。然而，ABL 维持血钙水平稳定的机制仍知之甚少。我们的体内数据表明，ABL 治疗（40μg/kg/天，持续 7 天）可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，而不会升高血钙值。ABL 还显著增加了由成骨细胞合成的血液和骨骼中的羧化骨钙素（Gla-Ocn），并增加了非羧化的 Ocn，由于破骨细胞的激活，非羧化的 Ocn 从骨基质释放到循环中。体外数据表明，ABL（10nM，持续 24 小时）对非肾脏细胞（大鼠成骨样细胞）中 1,25-(OH)2D 合成和 Gla-Ocn 形成的直接作用很小。然而，当向细胞中添加 1α-羟化酶的底物 25-羟维生素 D 时，ABL 显著促进了 1,25-(OH)2D 和 Gla-Ocn 的形成。因此，在接受 ABL 治疗的大鼠中，1,25-(OH)2D 水平的升高导致循环中 Gla-Ocn 和钙的短暂增加。Gla-Ocn 随后介导细胞外液中的钙离子与骨表面的羟磷灰石结合。这种由 Gla-Ocn 调节的机制至少部分维持了 ABL 治疗期间血钙水平的稳定。我们得出结论，ABL/1,25-(OH)2D/Gla-Ocn 的信号通路有助于钙稳态，并可能有助于理解 ABL 治疗骨质疏松症的机制。
