Female estrogen receptor beta-/- mice are partially protected against age-related trabecular bone loss.

Recently, it has been shown that inactivation of estrogen receptor beta (ER-beta) by gene targeting results in increased cortical bone formation in adolescent female mice. To study the possible involvement of ER-beta in the regulation of the mature skeleton, we have extended the analyses to include 1-year-old ER-beta knockout mice (ER-beta-/-). Male ER-beta-/- mice did not express any significant bone phenotypic alterations at this developmental stage. However, the increase in cortical bone parameters seen already in the adolescent female ER-beta-/- mice was maintained in the older females. The aged female ER-beta-/- mice further exhibited a significantly higher trabecular bone mineral density (BMD) as well as increased bone volume/total volume (BV/TV) compared with wild-type (wt) mice. This was caused by a less pronounced loss of trabecular bone during adulthood in female ER-beta-/- mice. The growth plate width was unaltered in the female ER-beta-/- mice. Judged by the expression of the osteoclast marker tartrate-resistant acid phosphatase (TRAP) and cathepsin K (cat K; reverse-transcription-polymerase chain reaction [RT-PCR]) as well as the serum levels of C-terminal type I collagen cross-linked peptide, bone resorption appeared unaffected. However, an increase in the messenger RNA (mRNA) expression levels of the osteoblast marker core-binding factor alpha1 (Cbfa1) suggested an anabolic effect in bones of old female ER-beta-/- mice. In addition, the mRNA expression of ER-alpha was augmented, indicating a role for ER-alpha in the development of this phenotype. Taken together, the results show that ER-beta is involved in the regulation of trabecular bone during adulthood in female mice and suggest that ER-beta acts in a repressive manner, possibly by counteracting the stimulatory action of ER-alpha on bone formation.

Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice.

Androgens may regulate the male skeleton directly through a stimulation of androgen receptors or indirectly through aromatization of androgens into estrogen and, thereafter, through stimulation of estrogen receptors (ERs). The relative importance of ER subtypes in the regulation of the male skeleton was studied in ERalpha-knockout (ERKO), ERbeta-knockout (BERKO), and double ERalpha/beta-knockout (DERKO) mice. ERKO and DERKO, but not BERKO, demonstrated decreased longitudinal as well as radial skeletal growth associated with decreased serum levels of insulin-like growth factor I. Therefore, ERalpha, but not ERbeta, mediates important effects of estrogen in the skeleton of male mice during growth and maturation.