Inactivation of estrogen receptor α in bone-forming cells induces bone loss in female mice

The role of the estrogen receptor alpha (ER alpha) in bone-forming cells is incompletely understood at present. To examine the in vivo effects of ER alpha in these cells, we generated a mouse strain in which the ER alpha gene is inactivated in osteoblasts via osteocalcin promoter-regulated cyclic recombinase (Cre) activity (ER alpha(Delta OB/Delta OB)). This enabled micro-computed tomography- and histomorphometry-based analysis of ER alpha-mediated effects in bone-forming cells in mice, in which the systemic ER alpha-mediated effects are intact. In female ER alpha(Delta OB/Delta OB) mice, trabecular and cortical bone volumes were significantly reduced (31.5 and 11.4%, respectively) at 3.5 mo of age compared with control ER alpha(fl/fl) animals, and their response to ovariectomy was small compared with that of controls. In contrast with females, no differences could be detected in the bone phenotype of young males, whereas in 6-mo-old ER alpha(Delta OB/Delta OB) males, trabecular bone volume (Tb.BV) was decreased (27.5%). The ER alpha inactivation-related effects were compared with those of controls having a similar genetic background. Parental osteocalcin-Cre mice did not show Cre-related changes. Our results suggest that in female mice, Tb.BV and cortical bone volume are critically dependent on the ER alpha regulation of osteoblasts, whereas in male mice, osteoblastic ER alpha is not required for the regulation of bone formation during rapid skeletal growth, but it is involved in the maintenance of Tb.BV.-Maatta, J. A., Buki, K. G., Gu, G., Alanne, M. H., Vaaraniemi, J., Liljenback, H., Poutanen, M., Harkonen, P., Vaananen, K. Inactivation of estrogen receptor alpha in bone-forming cells induces bone loss in female mice. FASEB J. 27, 478-488 (2013). www.fasebj.org