Xu Wen-Ning, Zheng Huo-Liang, Yang Run-Ze, Jiang Lei-Sheng, Jiang Sheng-Dan
Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2020 Jan 28;10:922. doi: 10.3389/fendo.2019.00922. eCollection 2019.
Long-term and high dose glucocorticoid treatment can cause decreased viability and function of osteoblasts, which leads to osteoporosis and osteonecrosis. In this study, we investigated the role and mechanism of action of HIF-1α in glucocorticoid-induced osteogenic inhibition in MC3T3-E1 cells. Our results showed that HIF-1α protein expression was reduced when MC3T3-E1 cells were exposed to dexamethasone (Dex) at varying concentrations ranging from 10 to 10 M. PDK1 expression was also decreased in MC3T3-E1 cells after dexamethasone treatment. MC3T3-E1 cells when treated with the glucocorticoid receptor antagonist RU486 along with dexamethasone showed enhanced HIF-1α expression. In addition, upregulated expression of HIF-1α was capable of promoting the osteogenic ability of MC3T3-E1 cells and PDK1 expression. However, the HIF-1α antagonist 2-methoxyestradiol (2-ME) had a reverse effect in MC3T3-E1 cells exposed to dexamethasone. Furthermore, the PDK1 antagonist dichloroacetate could repress the osteogenic ability of MC3T3-E1 cells, although HIF-1α was upregulated when transduced with adenovirus-HIF-1α construct. The PDK1 agonist PS48 was able to promote the osteogenic ability of MC3T3-E1 cells treated with dexamethasone. Importantly, the protein levels of p-AKT and p-mTOR were increased in MC3T3-E1 cells treated with dexamethasone after PS48 treatment. , the PDK1 agonist PS48 could maintain the bone mass of mice treated with dexamethasone. This study provides a new understanding of the mechanism of glucocorticoid-induced osteoporosis.
长期大剂量糖皮质激素治疗可导致成骨细胞活力和功能下降，进而引发骨质疏松和骨坏死。在本研究中，我们探讨了缺氧诱导因子-1α（HIF-1α）在糖皮质激素诱导的MC3T3-E1细胞成骨抑制中的作用及作用机制。我们的结果显示，当MC3T3-E1细胞暴露于浓度范围为10至10 μM的地塞米松（Dex）时，HIF-1α蛋白表达降低。地塞米松处理后，MC3T3-E1细胞中丙酮酸脱氢酶激酶1（PDK1）的表达也降低。当MC3T3-E1细胞与糖皮质激素受体拮抗剂RU486和地塞米松一起处理时，HIF-1α表达增强。此外，HIF-1α表达上调能够促进MC3T3-E1细胞的成骨能力和PDK1表达。然而，HIF-1α拮抗剂2-甲氧基雌二醇（2-ME）对暴露于地塞米松的MC3T3-E1细胞具有相反的作用。此外，尽管用腺病毒-HIF-1α构建体转导时HIF-1α上调，但PDK1拮抗剂二氯乙酸可抑制MC3T3-E1细胞的成骨能力。PDK1激动剂PS48能够促进用地塞米松处理的MC3T3-E1细胞的成骨能力。重要的是，PS48处理后，用地塞米松处理的MC3T3-E1细胞中磷酸化蛋白激酶B（p-AKT）和磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）的蛋白水平升高。此外，PDK1激动剂PS48可维持用地塞米松处理的小鼠的骨量。本研究为糖皮质激素诱导的骨质疏松症的机制提供了新的认识。
