RRC ID 42618
Author Maran A, Gorny G, Oursler MJ, Zhang M, Shogren KL, Yaszemski MJ, Turner RT.
Title 2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts.
Journal J Cell Biochem
Abstract 2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17beta-estradiol, is highly cytotoxic to a wide range of tumor cells but is harmless to most normal cells. However, 2-ME prevented bone loss in ovariectomized rats, suggesting it inhibits bone resorption. These studies were performed to determine the direct effects of 2-ME on cultured osteoclasts. 2-ME (2 microM) reduced osteoclast number by more than 95% and induced apoptosis in three cultured osteoclast model systems (RAW 264.7 cells cultured with RANKL, marrow cells co-cultured with stromal support cells, and spleen cells cultured without support cells in media supplemented with RANKL and macrophage colony stimulating factor (M-CSF)). The 2-ME-mediated effect was ligand specific; 2-hydroxyestradiol (2-OHE), the immediate precursor to 2-ME, exhibited less cytotoxicity; and 2-methoxyestrone (2-MEOE1) the estrone analog of 2-ME, was not cytotoxic. Co-treatment with ICI 182,780 did not antagonize 2-ME, suggesting that the cytotoxicity was not estrogen receptor-dependent. 2-ME-induced cell death in RAW 264.7 cells coincided with an increase in gene expression of cytokines implicated in inhibition of differentiation and induction of apoptosis. In addition, the 2-ME-mediated decrease in cell survival was partially inhibited by anti-lymphotoxin(LT)beta antibodies, suggesting that 2-ME-dependent effects involve LTbeta. These results suggest that 2-ME could be useful for treating skeletal diseases in which bone resorption is increased, such as postmenopausal osteoporosis and cancer metastasis to bone.
Volume 99(2)
Pages 425-34
Published 2006-10-1
DOI 10.1002/jcb.20924
PMID 16619269
MeSH 2-Methoxyestradiol Animals Apoptosis / drug effects Bone Resorption / prevention & control Cell Differentiation / drug effects Cell Line Cell Survival / drug effects Cells, Cultured Cytokines / genetics Estradiol / analogs & derivatives* Estradiol / pharmacology Estrogen Receptor Modulators / pharmacology Female Fulvestrant Lymphotoxin-alpha / antagonists & inhibitors Lymphotoxin-beta Membrane Proteins / antagonists & inhibitors Mice Osteoclasts / cytology* Osteoclasts / drug effects* Osteoclasts / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Rats
IF 4.237
Times Cited 19
Human and Animal Cells ST2(RCB0224)