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This version published online on November 6, 2003
Endocrinology, doi:10.1210/en.2003-1014
A more recent version of this article appeared on February 1, 2004
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Submitted on August 6, 2003
Accepted on October 28, 2003

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

M. Heim1, O. Frank1, G. Kampmann1, N. Sochocky1, T. Pennimpede1, P. Fuchs1, W. Hunziker1, P. Weber1, I. Martin1, and I. Bendik1*

1 Roche Vitamins Ltd, Human Nutrition & Health, Research and Development, CH-4070 Basel, Switzerland.; University of Freiburg i.Br., Institute of Biology II, Cell Biology, D-79104 Freiburg, Germany.; Departments of Surgery and Research, University Hospital Basel, CH-4031 Basel, Switzerland

* To whom correspondence should be addressed. E-mail: igor.bendik{at}roche.com.

In the present study we investigated the role of the phytoestrogen genistein and 17{beta}-estradiol (E2) in human bone marrow stromal cells (BMSCs), undergoing induced osteogenic or adipogenic differentiation. Profiling of estrogen receptors (ER) {alpha}, {beta}1, {beta}2, {beta}3, {beta}4, {beta}5 and aromatase mRNAs revealed lineage-dependent expression patterns. During osteogenic differentiation the osteoblast-determining core binding factor {alpha}1 (Cbfa-1) showed a progressive increase, whereas the adipogenic regulator peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) 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 (ALP) mRNA levels and activity, the OPG/RANKL gene expression ratio, and the expression of transforming growth factor {beta}1 (TGF{beta}1). During adipogenic differentiation, downregulation in the mRNA levels of PPAR{gamma} and C/EBP{alpha} at day 3, and decreased lipoprotein lipase (LPL) and adipsin mRNA levels at day 21, were observed following genistein treatment. This led to a lower number of adipocytes and to a reduction in the size of their lipid droplets. At day 3 of adipogenesis TGF{beta}1 was strongly upregulated by genistein, in a ER-dependent manner. Blocking the TGF{beta}1 pathway abolished the effects of genistein on PPAR{gamma} protein levels, and led to a reduction in the proliferation rate of precursor cells. Overall, genistein enhanced the commitment and differentiation of BMSCs 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 E2) via an ER-dependent mechanism involving autocrine or paracrine TGF{beta}1 signaling.
Key words: mesenchymal stem cell • lineage commitment • transforming growth factor {beta}1 (TGF{beta}1) • soy isoflavone • estrogen receptor (ER) • adipocyte • osteoblast




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