Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells
- 作者：Anu Kallio ; Tao Guo ; Elisa Lamminen ; Jani Seppä ; nen ; Lauri Kangas ; H. Kalervo Vä ; ä ; nä ; nen ; Pirkko Hä ; rkö ; nen
- 关键词：Osteoblast ; U2OS ; Estradiol ; Estrogen receptor ; OPG ; IL-6
- 刊名：Molecular and Cellular Endocrinology
- 出版年：2008
- 期刊代码：109_03037207
- 类别：bio
- 出版时间：16 July 2008
- 卷：289
- 期：1-2
- 页码：38-48
- 文件大小：1129 K
摘要
In the current work, we compared the ability of 17β-estradiol (E2) and the selective estrogen receptor modulators (SERMs), tamoxifen (Tam), raloxifene (Ral) and ospemifene (Osp) to promote the survival of osteoblast-derived cells against etoposide-induced apoptosis. In order to compare the roles of the two estrogen receptor (ER) isotypes, we created a U2OS human osteosarcoma cell line stably expressing either ERalpha (ER
) or ERbeta (ERβ). Transfection with either of the ERs was able to render the U2OS cells sensitive to E2. We show that E2 opposed etoposide-induced apoptosis and that the effect was mediated via both ER isotypes. The ER isotype selective agonists propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN) had the same effect in U2OS/ER and U2OS/ERβ cells, respectively. Osp also opposed apoptosis at least in U2OS/ER cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E2 and Osp upon etoposide challenge, we studied the expression of two E2-regulated, osteoblast-produced cytokines, IL-6 and OPG in E2 and SERM-treated U2OS/ER and U2OS/ERβ cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG. E2 opposed IL-6 increase only in U2OS/ER cells and OPG decrease primarily in ERβ cells. Osp opposed the effect of etoposide on OPG primarily in U2OS/ERβ cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposide-induced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ER and ERβ. Collectively, our results suggest that the osteoblast protective anti-apoptotic effects of E2 are mediated by both ER and ERβ but those of Osp primarily by ER. In addition, E2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These anti-resorptive effects of E2 and Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ER and ERβ expressing osteoblast-derived U2OS cells.
) or ERbeta (ERβ). Transfection with either of the ERs was able to render the U2OS cells sensitive to E2. We show that E2 opposed etoposide-induced apoptosis and that the effect was mediated via both ER isotypes. The ER isotype selective agonists propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN) had the same effect in U2OS/ER and U2OS/ERβ cells, respectively. Osp also opposed apoptosis at least in U2OS/ER cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E2 and Osp upon etoposide challenge, we studied the expression of two E2-regulated, osteoblast-produced cytokines, IL-6 and OPG in E2 and SERM-treated U2OS/ER and U2OS/ERβ cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG. E2 opposed IL-6 increase only in U2OS/ER cells and OPG decrease primarily in ERβ cells. Osp opposed the effect of etoposide on OPG primarily in U2OS/ERβ cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposide-induced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ER and ERβ. Collectively, our results suggest that the osteoblast protective anti-apoptotic effects of E2 are mediated by both ER and ERβ but those of Osp primarily by ER. In addition, E2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These anti-resorptive effects of E2 and Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ER and ERβ expressing osteoblast-derived U2OS cells.