2-methoxyestradiol Inhibits Differentiation and is Cytotoxic to Osteoclasts.
From: Department of Orthopedics, Mayo Clinic, Rochester, Minnesota 55905, USA. maran@mayo.edu
Journal of cellular biochemistry
- Publish Date: Oct 2006
- ISSN: 0730-2312
- Volume: 99
- Issue: 2
- Pages: 425-34
- Medium: Print
- Language: English
- Citation (JAMA): Maran A, Gorny G, Oursler M J, et al. 2-methoxyestradiol Inhibits Differentiation and is Cytotoxic to Osteoclasts.. J. Cell. Biochem. Oct 2006;99:425-34
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.
Mesh Headings (Keywords): Animals, Apoptosis, Bone Resorption, Cell Differentiation, Cell Line, Cell Survival, Cells, Cultured, Cytokines, Estradiol, Estrogen Receptor Modulators, Female, Lymphotoxin-alpha, Lymphotoxin-beta, Membrane Proteins, Mice, Osteoclasts, RNA, Messenger, Rats
Check for Full Text / PubMed Unique Identifier (PMID): 16619269
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