This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Transfection with either of the ERs was able to render the U2OS cells sensitive to E 2 . Weshow that E 2 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/ERα and U2OS/ER cells, respectively. Osp also opposed apoptosis at least in U2OS/ERα cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E 2 and Osp upon etoposide challenge we studied the expression of two E 2 -regulated, osteoblast-produced cytokines, IL-6 and OPG in E 2 and SERM-treated U2OS/ERα and U2OS/ER cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG.E 2 opposed IL-6 increase only in U2OS/ERα cells and OPG decrease primarily in ER cells.Osp opposed the effect of etoposide on OPG primarily in U2OS/ER cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposideinduced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ERα and ER. Collectively, our results suggest that the osteoblast protective antiapoptotic effects of E 2 are mediated by both ERα and ER but those of Osp primarily by ER. In addition, E 2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These antiresorptive effects of E 2 andPage 3 of 53 A c c e p t e d M a n u s c r i p t 2 Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ERα and ER expressing osteoblast-derived U2OS cells.