Estrogen modulates estrogen receptor alpha and beta expression, osteogenicactivity, and apoptosis in mesenchymal stem cells (MSC) of osteoporotic mice

in the mouse, ovariectomy (OVX) leads to significant reductions in cancello us bone volume while estrogen (17 beta -estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent in crease in bone formation would require the proliferation and differentiatio n of osteoblast precursors, we hypothesized that E? regulates mesenchymal s tem cells (MSCs) activity in mouse bone marrow. We therefore investigated p roliferation, differentiation, apoptosis, and estrogen receptor (:ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-ope rated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significan t increase in ER alpha mRNA and protein expression as well as alkaline phos phatase (ALP) activity and proliferation rate. In contrast, E2 treatment re sulted in a decrease in ER beta mRNA and protein expression as well as apop tosis in both OVX and sham m ice. E2 up-regulated the mRNA expression of os teogenic genes for ALP, collagen I, TGF-beta1, BMP-2, and cbfa1 in MSCs. In a comparison of the relative mRNA expression and protein levels for two ER isoforms, ER alpha was the predominant form expressed in MSCs obtained fro m both OVX and sham-operated mice. Cumulatively, these results indicate tha t estrogen in vitro directly augments the proliferation and differentiation , ER alpha expression, osteogenic gene expression and, inhibits apoptosis a nd ERP expression in MSCs obtained from OVX and sham-operated mice. Coexpre ssion of ER alpha, but not ER beta, and osteogenic differentiation markers might indicate that ER I function as an activator and ERP function as a rep ressor in the osteogenic differentiation in MSCs. These results suggest tha t mouse MSCs are anabolic targets of estrogen action, via ER alpha activati on. (C) 2001 Wiley-Liss, Inc.