Estrogen modulates estrogen receptor α and β expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSC) of osteoporotic mice

in the mouse, ovariectomy (OVX) leads to significant reductions in cancellous bone volume while estrogen (17 beta -estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent increase in bone formation would require the proliferation and differentiation of osteoblast precursors, we hypothesized that E? regulates mesenchymal stem cells (MSCs) activity in mouse bone marrow. We therefore investigated proliferation, differentiation, apoptosis, and estrogen receptor (:ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-operated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significant increase in ER alpha mRNA and protein expression as well as alkaline phosphatase (ALP) activity and proliferation rate. In contrast, E2 treatment resulted in a decrease in ER beta mRNA and protein expression as well as apoptosis in both OVX and sham m ice. E2 up-regulated the mRNA expression of osteogenic 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 from both OVX and sham-operated mice. Cumulatively, these results indicate that estrogen in vitro directly augments the proliferation and differentiation, ER alpha expression, osteogenic gene expression and, inhibits apoptosis and ERP expression in MSCs obtained from OVX and sham-operated mice. Coexpression 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 repressor in the osteogenic differentiation in MSCs. These results suggest that mouse MSCs are anabolic targets of estrogen action, via ER alpha activation. (C) 2001 Wiley-Liss, Inc.