ESTROGEN PROMOTES APOPTOSIS OF MURINE OSTEOCLASTS MEDIATED BY TGF-BETA

Postmenopausal osteoporosis, the most common bone disease in the devel oped world(1), is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perfo rate bone trabeculae, thus reducing their strength and increasing frac ture risk. Estrogen replacement prevents these effects(2), indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life sp an and thus the amount of bone that osteoclasts resorb could also be e nhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues(3), we investigated whether estroge n may affect osteoclast function by promoting apoptosis. 17 beta-Estra diol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone res orption(4), and transforming growth factor-beta 1 (TGF-beta), whose pr oduction by osteoblasts is increased by estrogen(5), had similar effec ts in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta migh t mediate this effect. These findings suggest that estrogen may preven t excessive bone loss before and after the menopause by limiting osteo clast life span through promotion of apoptosis. The development of ana logues to promote this mechanism specifically could be a useful and no vel therapeutic approach to prevent postmenopausal osteoporosis.