2-Methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts

A. Maran, G. Corny, M. J. Oursler, M. Zhang, K. L. Shogren, M. J. Yaszemski, R. T. Turner

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20 Scopus citations


2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17β-estradiol, is highly cytotoxicto 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 μM) 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)β antibodies, suggesting that 2-ME-dependent effects involve LTβ. 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.

Original languageEnglish (US)
Pages (from-to)425-434
Number of pages10
JournalJournal of cellular biochemistry
Issue number2
StatePublished - Oct 1 2006


  • Apoptosis
  • Bone resorption
  • Cytokines
  • Estrogen metabolite

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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