Estrogen receptor specificity in the regulation of the skeleton in female mice

Abstract

There are two known estrogen receptors, estrogen receptor-(ER ) and estrogen receptor-(ER ), which may mediate the actions of estrogen. The aim of the present study was to compare fat content, skeletal growth and adult bone metabolism in female mice lacking ER (ERKO), ER (BERKO) or both ERs (DERKO). We demonstrate that endogenous estrogens decrease the fat content in female mice via ER and not ER . Interestingly, the longitudinal bone growth was decreased in ERKO, increased in BERKO, but was intermediate in DERKO females, demonstrating that ER and ER exert opposing effects in the regulation of longitudinal bone growth. The effects on longitudinal bone growth were correlated with similar effects on serum levels of IGF-I. A complex regulation of the trabecular bone mineral density (BMD), probably caused by a disturbed feedback regulation of estrogen and testosterone, was observed in female ER-inactivated mice. Nevertheless, a partial functional redundancy for ER and ER in the maintenance of the trabecular BMD was observed in the female mice at 60 days of age. Thus, ER and ER may have separate effects (regulation of fat), opposing effects (longitudinal bone growth) or partial redundant effects (trabecular BMD at 60 days of age), depending on which parameter is studied.

Estrogen receptor subtype-specific effects on markers of bone homeostasis

“…In line with previous findings from our laboratory, our data shows that OVX rats display a stronger increase of body weight compared to E 2 and SHAM rats mainly due to an increase in the percentage of total body fat (Lindberg et al 2001a, Hertrampf et al 2007). In contrast to treatment with 8-VE2, application of 16-LE2 resulted in an antagonization of body weight increase after OVX (Fig.…”

“…These data are in agreement with studies performed in knockout mice: application of E 2 did not prevent the development of osteoporosis in ERKO female (Lindberg et al 2001a, Lindberg et al 2002a) and male mice (Lindberg et al 2002b), indicating that the bone-protective effects of E 2 are primarily mediated by ER. Further, ERα gene polymorphisms are associated with osteoporosis in human populations (Gómez et al 2007).…”

“…Opposing effects were observed for longitudinal bone growth after activation of ERα and ERβ (Windahl et al 1999, Lindberg et al 2001a, suggesting a repressive function for ERβ in the regulation of bone growth during adolescence.…”

“…This is in agreement with studies using male and female ER knockout mice (ERKO). In these animals A c c e p t e d M a n u s c r i p t of body weight and composition in wild type animals with natural ratios of both ER subtypes is also mainly mediated via ER (Fig.2 B) (Lindberg et al 2001a, Hertrampf et al 2007). …”

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

“…Several SERMs are well known to protect against bone loss related to the menopause-related deficit in estrogen, and a wide variety of studies in multiple species and conditions have demonstrated the efficacy of SERMs to reduce bone turnover, and to prevent bone or BMD loss. 31,32,45,46 The effect of estrogen on BMD is ERa-dependent, 21 and the ERa and ERb appear to exert opposing actions: 47 activation of the ERa promotes longitudinal bone growth, whereas that of the ERb represses it. In the present study, substantial changes in BMD over a 28-day period in 5-month-old mice were obviously not expected, but the data nevertheless point to interesting trends.…”