2-Methoxyestradiol Inhibits Longitudinal Bone Growth in Normal Female Rats

Abstract

2-Methoxyestradiol (2-MeO-E(2)), a major metabolite of 17beta-estradiol, may function as a physiological tumor suppressor and is being investigated for clinical applications. It has been reported to target rapidly dividing cells. We investigated the effects of 2-MeO-E(2) on the growth plate of young rats because normal longitudinal bone growth requires rapid proliferation of cartilage and endothelial cells. Sexually mature (3-month-old) normal female rats were treated with 2-MeO-E(2) (100 mg/kg/day) for 13 days and it was found to have no effect on uterine weight but reduced serum cholesterol. The estrogen metabolite had no effect on either cortical or cancellous bone. In contrast, 2-MeO-E(2) dramatically reduced longitudinal bone growth rate at the proximal tibia from 55 +/- 2 to 20 +/- 2 microm/day (P < 0.001) and growth plate thickness from 153 +/- 14 to 70 +/- 6 microm (P < 0.001). The latter decrease was due to significant reductions in the height of both the proliferative (P < 0.001) and the hypertrophic (P < 0.001) zones. These results in normal female rats demonstrate that 2-MeO-E(2) inhibited longitudinal bone growth but had no effect on either radial bone growth or cancellous bone turnover. 2-MeO-E(2) was shown by these studies to have the ability to discriminate between bone and cartilage, as well as between reproductive and nonreproductive estrogen-target tissues. Thus, 2-MeO-E(2) is a naturally produced estrogen metabolite that demonstrates unique tissue selectivity.