2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts

✍ Scribed by A. Maran; G. Gorny; M.J. Oursler; M. Zhang; K.L. Shogren; M.J. Yaszemski; R.T. Turner

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 202 KB
• Volume: 99
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20924

✦ Synopsis

Abstract

2‐Methoxyestradiol (2‐ME), a naturally occurring metabolite of 17β‐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 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‐MEOE~1~) 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. J. Cell. Biochem. 99: 425–434, 2006. © 2006 Wiley‐Liss, Inc.