caa a22 4500 605463123 CHVBK 20210128100251.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00774-014-0627-1 doi (NATIONALLICENCE)springer-10.1007/s00774-014-0627-1 Hypoxia enhances glucocorticoid-induced apoptosis and cell cycle arrest via the PI3K/Akt signaling pathway in osteoblastic cells [Elektronische Daten] [Wanjing Zou, Shu Yang, Tie Zhang, Haimei Sun, Yuying Wang, Hong Xue, Deshan Zhou] Although osteonecrosis of the femoral head is a known primary limitation of long-term or high-dose clinical administration of glucocorticoids, the mechanisms underlying this side effect remain unclear. Hypoxia is an important biological state under numerous pathological conditions. In this study, we investigated glucocorticoid-induced osteonecrosis under hypoxic conditions in the MC3T3-E1 osteoblast cell line using a cell cytotoxicity assay, flow cytometry, and western blotting. 6α-Methylprednisolone sodium succinate (MPSL) more effectively induced apoptosis and G0/G1 arrest of MC3T3-E1 osteoblasts under hypoxic conditions than under normoxic conditions. Correspondingly, MPSL more effectively upregulated cellular levels of cleaved caspase3, p53, and its target p21, and downregulated cyclin D1 levels in hypoxia. Moreover, overexpression of Akt abrogated the MPSL activation of p53, p21, and cleaved caspase 3 and the attenuation of cyclin D1 expression and rescued osteoblasts from MPSL-induced cell cycle arrest and apoptosis, indicating that phosphatidylinositol 3-kinase (PI3K)/Akt signaling might play an essential role in MPSL-induced inhibition of osteoblasts. Furthermore, the suppression of PI3K/Akt signaling and upregualtion of cellular p85α monomer levels by MPSL were more pronounced under hypoxic conditions than under normoxic conditions. Finally, we found that the enhancement of the effects of MPSL under hypoxic conditions was attributed to hypoxia-upregulated glucocorticoid receptor activity. In conclusion, our results demonstrate that MPSL, a synthetic glucocorticoid receptor agonist, promotes the level of p85α and inhibits PI3K/Akt signaling to induce apoptosis and cell cycle arrest in osteoblasts, and that this effect is enhanced under hypoxic conditions. The Japanese Society for Bone and Mineral Research and Springer Japan, 2014 Glucocorticoid nationallicence Hypoxia nationallicence Osteoblast nationallicence Apoptosis nationallicence Cell cycle arrest nationallicence Zou Wanjing Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Yang Shu Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Zhang Tie Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Sun Haimei Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Wang Yuying Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Xue Hong Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Zhou Deshan Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut Journal of Bone and Mineral Metabolism Springer Japan 33/6(2015-11-01), 615-624 0914-8779 33:6<615 2015 33 774 https://doi.org/10.1007/s00774-014-0627-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00774-014-0627-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zou Wanjing Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Yang Shu Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Tie Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Sun Haimei Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Wang Yuying Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Xue Hong Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 700 1- Zhou Deshan Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, People's Republic of China aut NATIONALLICENCE 773 0- Journal of Bone and Mineral Metabolism Springer Japan 33/6(2015-11-01), 615-624 0914-8779 33:6<615 2015 33 774