Estrogen replacement therapy prevents bone loss, in part. by promoting osteoclast apoptosis

B. F. Boyce, D. E. Hughes, J. Tiffee, H. H. Li, A. Dai, G. R. Mundy

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Abstract

Postmenopausal osteoporosis, the commonest bone disease in the developed world, is associated with estrogen deficiency. This induces increased generation and activity of bone-resorbing osteoclasts which perforate bone trabeculae thus reducing their strength and increasing fracture risk. Estrogen replacement therapy prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Since functional osteoclast life span and thus the amount of bone osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis in vivo and in vitro. Viable and apoptotic osteoclasts were identified using standard morphological criteria. Apoptosis was confirmed using TUNEL and/or acridine orange. Treatment of ovariectomized mice for 1 or 3 weeks with 17 beta-estradiol reduced osteoclast numbers, increased osteoclast apoptosis and prevented ovariectomy-induced bone loss. Osteoclasts were generated from mouse bone marrow cell cultures over 7 days and treated with test substances for a further 24h. 17 beta -estradiol caused a 2-3 fold increase in osteoclast apoptosis. Tamoxifen, which has estrogenic effects on bone résorption, and transforming growth factor beta 1 (TGF beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF beta antibody inhibited estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogs to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.

Original languageEnglish (US)
Pages (from-to)613S
JournalBiochemical Society transactions
Volume24
Issue number4
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry

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