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Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) or ß

Third Department of Medicine (R.O., M.S., H.O., H.T., Y.S.), Teikyo University School of Medicine, Ichihara, Chiba 299-0111; First Department of Internal Medicine (D.I., M.S., S.K., T.M.), University of Tokushima School of Medicine, Tokushima 770-8530, Japan

Address all correspondence and requests for reprints to: Ryo Okazaki, M.D., Third Department of Medicine, Teikyo University School of Medicine, 3426-3 Anesaki, Ichihara, 299-0111 Japan. E-mail: . rokazaki{at}med.teikyo-u.ac.jp

Although cells of the osteoblast lineage express functional ERs, direct effects of estrogen on bone formation remain obscure. In the present study, we have investigated estrogen effects on osteoblastic and adipocytic differentiation from a mouse bone marrow stromal cell line, ST-2, which had been manipulated to overexpress either human ER (ST2ER) or ERß (ST2ERß). Treatment with bone morphogenetic protein-2 increased alkaline phosphatase activity as well as the number of Oil Red O-positive adipocytes, indicating that bone morphogenetic protein-2 stimulated both osteoblastic and adipocytic differentiation from these bipotential cells. In both ST2ER and ST2ERß cells, cotreatment with E2 caused enhancement of alkaline phosphatase activity and suppression of lipid accumulation. These effects were completely reversed by an ER antagonist, ICI182780. Therefore, the estrogen regulation occurred in an ER-specific manner but without ER subtype specificity. Moreover, dose response curves of the opposing effects of estrogen on osteoblastogenesis and adipogenesis formed an apparent mirror image, consistent with a reciprocal regulation of differentiation into the two cell lineages. These results demonstrate that estrogen directly modulates differentiation of bipotential stromal cells into the osteoblast and adipocyte lineages, causing a lineage shift toward the osteoblast. Such effects would lead to direct stimulation of bone formation and thereby contribute to the protective effects of estrogen on bone.

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