The Effect of Estrogen on Bone Requires Er␣ in Nonhematopoietic Cells but Is Enhanced by Er␣ in Hematopoietic Cells

The effect of estrogen on bone requires ER␣ in nonhematopoietic cells but is enhanced by ER␣ in hemato-poietic cells. The effects of estrogen on bone are mediated mainly via estrogen receptor (ER)␣. ER␣ in osteoclasts (hematopoietic origin) is involved in the trabecular bone-sparing effects of estrogen, but conflicting data are reported on the role of ER␣ in osteoblast lineage cells (nonhema-topoietic origin) for bone metabolism. Because Cre-mediated cell-specific gene inactivation used in previous studies might be confounded by nonspecific and/or incomplete cell-specific ER␣ deletion, we herein used an alternative approach to determine the relative importance of ER␣ in hematopoietic (HC) and nonhematopoietic cells (NHC) for bone mass. Chimeric mice with selective inactivation of ER␣ in HC or NHC were created by bone marrow transplantations of wild-type (WT) and ER␣-knockout (ER␣ Ϫ/Ϫ) mice. Estradiol treatment increased both trabecular and cortical bone mass in ovariecto-mized WT/WT (defined as recipient/donor) and WT/ER␣ Ϫ/Ϫ mice but not in ER␣ Ϫ/Ϫ /WT or ER␣ Ϫ/Ϫ /ER␣ Ϫ/Ϫ mice. However, estradiol effects on both bone compartments were reduced (ϳ50%) in WT/ ER␣ Ϫ/Ϫ mice compared with WT/WT mice. The effects of estradiol on fat mass and B lymphopoiesis required ER␣ specifically in NHC and HC, respectively. In conclusion, ER␣ in NHC is required for the effects of estrogen on both trabecular and cortical bone, but these effects are enhanced by ER␣ in HC. estrogen; estrogen receptor-␣; bone marrow transplantation; trabecu-lar bone; cortical bone ESTROGEN REGULATES VARIOUS BIOLOGICAL PROCESSES, and one important target tissue is bone. The reduction in estrogen levels seen at menopause is strongly associated with postmenopausal osteo-porosis, and low estrogen levels have also been associated with low bone mass and increased fracture risk in elderly men (8, 17, 26). The effects of estrogen are mediated primarily via the nuclear estrogen receptors (ERs) ER␣ and ER␤. ER␣ is the main mediator of the trabecular and cortical bone protective effects of estrogen (2, 23). ER␣ expression is found both in nonhematopoietic cells (NHC), including the bone-forming osteoblasts and osteocytes, which are of mesenchymal origin, and in hematopoietic cells (HC), including the bone-resorbing osteoclasts (27). Treatment with estrogen has beneficial effects on bone mass but is associated with several side effects. Therefore, it is important to determine the target cell(s) mediating the positive ER␣-mediated estrogenic effects on bone to be able to separate the positive estrogen effects on bone from the negative side effects. To determine the …