Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids

Abstract

Many of the actions of estrogens and androgens are not explained by their receptors interacting with DNA, but there is no firm evidence that these nongenotropic actions are biologically important. The authors recently demonstrated strong anti-apoptotic effects of sex steroids on mouse osteoblasts and osteocytes. They are mediated by alterations in signaling cascades that modulate the activity of transcription factors. These sex steroid effects are not gender specific; they require only the ligand-binding domain of the receptor. The effects can be consistently reproduced by estren (4-estren-3α,17β-diol), a synthetic compound lacking classic transcriptional activity. Studies in adult mice showed that 17β-estradiol (E2), dihydrotestosterone (DHT), and estren lessened osteoblastic apoptosis and stimulated osteoclastic apoptosis. The osteoblastic apoptosis induced by gonadectomy in the lumbar spine was prevented by a replacement dose of E2, DHT, or estren in both male and female mice. Estren, unlike E2, failed to stimulate in vitro transcription of the C3 gene in the uterus, which is mediated by estrogen response elements. Estren was at least as effective as E2 for preserving spinal and global bone mineral density in female mice. After ovariectomy, estren proved better than E2 in augmenting bone mineral density in the hindlimb. In addition, estren was at least as effective as DHT replacement in mice having orchidectomy, as reflected by greater compression strength. Closure of the bone marrow cavity was noted with a pharmacologic dose of E2 but not with estren. Histomorphometric analysis of the lumbar spine confirmed significantly greater cortical and trabecular width in ovariectomized mice treated with estren compared with others given E2. Estren-treated animals had more osteoblasts on the trabeculae, and these cells produced much more unmineralized matrix. Both estren and E2 decreased the rate of bone formation and numbers of osteoclasts compared with ovariectomized mice. In contrast to E2 or DHT, estren did not alter uterine or seminal vesicle weight in gonadectomized mice. These findings mean that it is possible to separate the skeletal effects of sex steroids from their reproductive effects. Mechanism-specific ligands such as estren may be preferable to estrogens for hormone replacement therapy (HRT), especially in view of increasing concern about the safety of current HRT regimens.