Estrogen receptor α, but not estrogen receptor β, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-κB ligand) ratio and serum interleukin-6 in male mice

Estrogens are important for the male skeleton. Osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), interleukin-6 (IL-6), IL-1 and tumor necrosis factor α (TNFα) have been suggested to be involved in the skeletal effects of estrogen. We treated orchidectomized mice with estradiol for 2 weeks and observed a 143% increase in the trabecular bone mineral density of the distal metaphysis of femur that was associated with a decreased OPG/RANKL mRNA ratio in vertebral bone. A similar decreased OPG/RANKL ratio was also seen after estrogen treatment of ovariectomized female mice. The effect of estrogen receptor (ER) inactivation on the OPG/RANKL ratio was dissected by using intact male mice lacking ERα (ERKO), ERβ (BERKO) or both receptors (DERKO). The expression of OPG was increased in ERKO and DERKO but not in BERKO male mice, resulting in an increased OPG/RANKL ratio. Furthermore, serum levels of IL-6 and tartrate-resistant acid phosphatase 5b (TRAP 5b) were decreased in ERKO and DERKO, but not in BERKO male mice. These results demonstrate that ERα, but not ERβ, is involved in the regulation of the vertebral OPG/RANKL ratio, serum levels of IL-6 and TRAP 5b in male mice.