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These studies were performed to determine the direct effects of 2\u2010ME on cultured osteoclasts. 2\u2010ME (2 \u00b5M) 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\u2010cultured with stromal support cells, and spleen cells cultured without support cells in media supplemented with RANKL and macrophage colony stimulating factor (M\u2010CSF)). The 2\u2010ME\u2010mediated effect was ligand specific; 2\u2010hydroxyestradiol (2\u2010OHE), the immediate precursor to 2\u2010ME, exhibited less cytotoxicity; and 2\u2010methoxyestrone (2\u2010MEOE<jats:sub>1<\/jats:sub>) the estrone analog of 2\u2010ME, was not cytotoxic. Co\u2010treatment with ICI 182,780 did not antagonize 2\u2010ME, suggesting that the cytotoxicity was not estrogen receptor\u2010dependent. 2\u2010ME\u2010induced 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\u2010ME\u2010mediated decrease in cell survival was partially inhibited by anti\u2010lymphotoxin(LT)\u03b2 antibodies, suggesting that 2\u2010ME\u2010dependent effects involve LT\u03b2. These results suggest that 2\u2010ME could be useful for treating skeletal diseases in which bone resorption is increased, such as postmenopausal osteoporosis and cancer metastasis to bone. J. Cell. Biochem. 99: 425\u2013434, 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.20924","type":"journal-article","created":{"date-parts":[[2006,4,17]],"date-time":"2006-04-17T23:04:04Z","timestamp":1145315044000},"page":"425-434","source":"Crossref","is-referenced-by-count":18,"title":["2\u2010methoxyestradiol inhibits differentiation and is cytotoxic to 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