2,4′-二羟基二苯甲酮通过刺激 β-连环蛋白信号通路发挥骨形成和抗骨质疏松活性,ACS Pharmacology & Translational Science

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2,4′-二羟基二苯甲酮通过刺激 β-连环蛋白信号通路发挥骨形成和抗骨质疏松活性
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2024-01-19 , DOI: 10.1021/acsptsci.3c00251
Mirissa Hewage Dumindu Kavinda ₁ , Mi-Hwa Lee ₂ , Chang-Hee Kang ₂ , Yung Hyun Choi ₃ , Gi-Young Kim ₁

Affiliation

2,4′-二羟基二苯甲酮(DHP)是一种源自黄花藤黄果的有机化合物，但其生化功能和生物利用度尚未见报道。在本研究中，我们评估了 DHP 是否影响 MC3T3-E1 前成骨细胞的成骨细胞分化和激活，以及斑马鱼幼虫的抗骨质疏松活性。DHP 处理的 MC3T3-E1 前成骨细胞的无毒浓度以浓度依赖性方式增加碱性磷酸酶 (ALP) 活化和矿化，同时伴随着成骨细胞特异性标记物的更高表达，包括 Runt 相关转录因子 2 (RUNX2)、osterix、和碱性磷酸酶。与 MC3T3-E1 前成骨细胞中的数据一致，DHP 上调斑马鱼幼虫中成骨细胞特异性标记基因，同时增强椎骨形成。我们还发现，DHP 增加了糖原合成酶激酶-3β (GSK-3β) Ser9 的磷酸化和细胞质中 β-连环蛋白的总表达，并显着增加了 β-连环蛋白在细胞核中的定位。此外，DHP 可以恢复泼尼松龙 (PDS) 引起的 ALP 活性和矿化以及成骨细胞特异性标志物表达的显着降低。在 PDS 处理的斑马鱼中，DHP 还通过恢复椎骨形成和成骨细胞相关基因表达来减轻 PDS 诱导的骨质疏松症。总而言之，这些结果表明 DHP 是一种潜在的骨合成代谢候选药物，可通过刺激成骨细胞分化来治疗骨质疏松症。

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2,4′-Dihydroxybenzophenone Exerts Bone Formation and Antiosteoporotic Activity by Stimulating the β-Catenin Signaling Pathway

2,4′-Dihydroxybenzophenone (DHP) is an organic compound derived from Garcinia xanthochymus, but there have been no reports on its biochemical functions and bioavailability. In this study, we evaluated whether DHP affects osteoblast differentiation and activation in MC3T3-E1 preosteoblast cells, as well as antiosteoporotic activity in zebrafish larvae. Nontoxic concentrations of DHP-treated MC3T3-E1 preosteoblast cells increased alkaline phosphatase (ALP) activation and mineralization in a concentration-dependent manner, accompanied by higher expression of osteoblast-specific markers, including Runt-related transcription factor 2 (RUNX2), osterix, and ALP. Consistent with the data in MC3T3-E1 preosteoblast cells, DHP upregulated osteoblast-specific marker genes in zebrafish larvae and simultaneously enhanced vertebral formation. We also revealed that DHP increased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 and the total expression of β-catenin in the cytosol and markedly increased the localization of β-catenin into the nucleus. Furthermore, DHP restored the prednisolone (PDS)-induced marked decrease in ALP activity and mineralization, as well as osteoblast-specific marker expression. In PDS-treated zebrafish, DHP also alleviated PDS-induced osteoporosis by restoring vertebral formation and osteoblast-related gene expression. Taken together, these results suggest that DHP is a potential osteoanabolic candidate for treating osteoporosis by stimulating osteoblast differentiation.

更新日期：2024-01-19

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