The effect of estrogen on bone requires ERɑ in nonhematopoietic cells but is enhanced by ERɑ in hematopoietic cells.

The effects of estrogen on bone is mainly mediated via estrogen receptor (ER)ɑ. ERɑ in osteoclasts (hematopoietic origin) is involved in the trabecular bone sparing effects of estrogen but conflicting data is reported on the role of ERɑ in osteoblast lineage cells (non-hematopoietic origin) for bone metabolism. As Cre-mediated cell-specific gene inactivation, used in previous studies, might be confounded by non-specific and/or incomplete cell-specific ERɑ deletion, we herein used an alternative approach to determine the relative importance of ERɑ in hematopoietic (HC) and non-hematopoietic cells (NHC) for bone mass. Chimeric mice with selective inactivation of ERɑ in HC or NHC were created by bone marrow transplantations of wild-type (WT) and ERɑ knock-out (ERɑ-/-) mice. Estradiol treatment increased both trabecular and cortical bone mass in ovariectomized WT/WT (defined as recipient/donor) and WT/ERɑ-/- mice but not in ERɑ-/-/WT or ERɑ-/-/ERɑ-/- mice. However, estradiol effects on both bone compartments were reduced (~50%) in WT/ERɑ-/- mice compared to WT/WT mice. The effects of estradiol on fat mass and B lymphopoiesis required ERɑ specifically in NHC and HC, respectively. In conclusion, ERɑ in NHC is required for the effects of estrogen on both trabecular and cortical bone but these effects are enhanced by ERɑ in HC. [ABSTRACT FROM AUTHOR]