A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Abstract

Although the role of estradiol in maintaining bone mass is well established, the relative contributions of the estradiol receptors ERα and ERβ and of the androgen receptor (AR) remain controversial. To determine the role of ERα-mediated, ERβ-mediated, and non–ER-mediated mechanisms in maintaining bone mass, gonadectomy and estradiol treatment were studied in ER-knockout mice. Estradiol treatment of ovariectomized ERαβ–/– mice failed to prevent bone loss, precluding significant effects of estradiol on bone through non–ER-signaling pathways. In contrast, estradiol prevented ovariectomy-induced bone loss in ERβ–/– mice, as in WT males and females, indicating that ERα is the major mediator of estradiol effects in bone. No response of bone to estradiol was detected in orchidectomized ERα–/– mice, suggesting estradiol cannot protect bone mass via the AR in vivo. In contrast to female ERαβ–/– and male ERα–/– mice, female ERα–/– mice were partially protected against ovariectomy-induced bone loss by estradiol, confirming that ERβ mediates estradiol effects in bone, but only in females and with a lower efficacy than ERα. We conclude that ERα is the main effector of estradiol’s protective function in bone in both male and female mice, and that, in its absence, AR is not sufficient to mediate this response

Sex hormones and their receptors in bone homeostasis: insights from genetically modified mouse models

“…In the female skeleton, ERαβ KO decreased bone mass, confirming that both ER subtypes function to maintain bone mass [22].…”

Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor

“…Finally, the similarity of melting point of ProStrakan estren (210°C) to that of Steraloid estren (206-207°C, according to the manufacturer) indicated that the crystalline structure of both compounds is the same. Anti-estrogen (PSK3668) and anti-androgen (RU58642) were administered at 10 mg/kg/d and 30 mg/kg/d, respectively, by daily subcutaneous injection, as previously described (27). In the dose-response experiments, WT male C57BL/6 mice were subjected to ORX and treated with slow-release pellets delivering estren-α (Steraloids, 7.0; 1.8 or 0.9 mg/mouse/35 days), DHT (Steraloids; 3.5 mg/mouse/35 days), or vehicle.…”

“…Peripheral quantitative CT. Densitometry was performed with the Stratec peripheral quantitative CT (pQCT) XCT Research SA + (software version 5.4B; Norland Medical Systems Inc.) operating at a resolution of 70 μm as previously described (27). Briefly, metaphyseal pQCT scans of dissected right tibiae were performed to measure trabecular bone mineral density.…”

Sex steroid metabolism in the regulation of bone health in men

“…Because of this possible dual mode of action of androgens, the contribution of androgens and estrogens in the regulation of the male skeleton remains complex. All three sex steroid receptors are expressed in bone cells [4], and experimental animal studies have shown that each of these three receptors mediates site-specific skeletal effects of sex steroids [5][6][7][8][9][10][11][12]. In addition, recent in vitro studies suggested that the membrane G proteincoupled receptor GPR30 might also be a potential estrogen receptor ( Fig.…”