School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Shandong Medicinal Biotechnology Center, Key Laboratory for Biotech-Drugs of the Ministry of Health, Jinan 250062, China.
Molecules. 2018 Oct 11;23(10):2600. doi: 10.3390/molecules23102600.
Isopsoralen (IPRN), one of the main effective ingredients in Linn, has a variety of biological effects, including antiosteoporotic effects. In vivo studies show that IPRN can increase bone strength and trabecular bone microstructure in a sex hormone deficiency-induced osteoporosis model. However, the mechanism underlying this osteogenic potential has not been investigated in detail. In the present study, we investigated the molecular mechanism of IPRN-induced osteogenesis in MC3T3-E1 cells. Isopsoralen promoted osteoblast differentiation and mineralization, increased calcium nodule levels and alkaline phosphatase (ALP) activity and upregulated osteoblast markers, including ALP, runt-related transcription factor 2 (RUNX2), and collagen type I alpha 1 chain (COL1A1). Furthermore, IPRN limited the nucleocytoplasmic shuttling of aryl hydrocarbon receptor (AhR) by directly binding to AhR. The AhR target gene cytochrome P450 family 1 subfamily A member 1 (CYP1A1) was also inhibited in vitro and in vivo. This effect was inhibited by the AhR agonists indole-3-carbinol (I3C) and 3-methylcholanthrene (3MC). Moreover, IPRN also increased estrogen receptor alpha (ERα) expression in an AhR-dependent manner. Taken together, these results suggest that IPRN acts as an AhR antagonist and promotes osteoblast differentiation via the AhR/ERα axis.
补骨脂素（IPRN）是补骨脂的主要有效成分之一，具有多种生物学效应，包括抗骨质疏松作用。体内研究表明，IPRN 可增加去势诱导骨质疏松模型中骨强度和小梁骨微结构。然而，其成骨潜能的机制尚未详细研究。本研究旨在探讨 IPRN 诱导 MC3T3-E1 细胞成骨的分子机制。补骨脂素促进成骨细胞分化和矿化，增加钙结节水平和碱性磷酸酶（ALP）活性，并上调成骨细胞标志物，包括 ALP、 runt 相关转录因子 2（RUNX2）和胶原 I 型α 1 链（COL1A1）。此外，IPRN 通过直接与 AhR 结合限制芳香烃受体（AhR）的核质穿梭。AhR 靶基因细胞色素 P450 家族 1 亚家族 A 成员 1（CYP1A1）也在体外和体内受到抑制。这种作用被 AhR 激动剂吲哚-3-甲醇（I3C）和 3-甲基胆蒽（3MC）抑制。此外，IPRN 还以 AhR 依赖的方式增加雌激素受体α（ERα）的表达。综上所述，这些结果表明，IPRN 作为 AhR 拮抗剂，通过 AhR/ERα 轴促进成骨细胞分化。
