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The Phytoestrogen Genistein Enhances Osteogenesis and Represses Adipogenic Differentiation of Human Primary Bone Marrow Stromal Cells

Human Nutrition and Health (M.H., G.K., N.S., W.H., T.P., P.F., P.W., I.B.), Research and Development, Roche Vitamins Ltd., CH-4070 Basel, Switzerland; Cell Biology (M.H.), Institute of Biology II, University of Freiburg i.Br., D-79104 Freiburg, Germany; and Departments of Surgery and Research (O.F., I.M.), University Hospital Basel, CH-4031 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Igor Bendik, Roche Vitamins Ltd., Human Nutrition and Health, VFHF, 205/219A, CH-4070 Basel, Switzerland. E-mail: igor.bendik{at}roche.com.

In the present study, we investigated the role of the phytoestrogen genistein and 17ß-estradiol in human bone marrow stromal cells, undergoing induced osteogenic or adipogenic differentiation. Profiling of estrogen receptors (ERs)-, -ß1, -ß2, -ß3, -ß4, -ß5, and aromatase mRNAs revealed lineage-dependent expression patterns. During osteogenic differentiation, the osteoblast-determining core binding factor-1 showed a progressive increase, whereas the adipogenic regulator peroxisome proliferator-activated receptor (PPAR) was sequentially decreased. This temporal regulation of lineage-determining marker genes was strongly enhanced by genistein during the early osteogenic phase. Moreover, genistein increased alkaline phosphatase mRNA levels and activity, the osteoprotegerin:receptor activator of nuclear factor-B ligand gene expression ratio, and the expression of TGFß1. During adipogenic differentiation, down-regulation in the mRNA levels of PPAR and CCAAT/enhancer-binding protein- at d 3 and decreased lipoprotein lipase and adipsin mRNA levels at d 21 were observed after genistein treatment. This led to a lower number of adipocytes and a reduction in the size of their lipid droplets. At d 3 of adipogenesis, TGFß1 was strongly up-regulated by genistein in an ER-dependent manner. Blocking the TGFß1 pathway abolished the effects of genistein on PPAR protein levels and led to a reduction in the proliferation rate of precursor cells. Overall, genistein enhanced the commitment and differentiation of bone marrow stromal cells to the osteoblast lineage but did not influence the late osteogenic maturation markers. Adipogenic differentiation and maturation, on the other hand, were reduced by genistein (and 17ß-estradiol) via an ER-dependent mechanism involving autocrine or paracrine TGFß1 signaling.

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