2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts

J Cell Biochem. 2006 Oct 1;99(2):425-34. doi: 10.1002/jcb.20924.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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


  • Cytokines
  • Estrogen Receptor Modulators
  • Ltb protein, mouse
  • Ltb protein, rat
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Membrane Proteins
  • RNA, Messenger
  • Fulvestrant
  • Estradiol
  • 2-Methoxyestradiol