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

Abstract

In the present study, we investigated the role of the phytoestrogen genistein and 17beta-estradiol in human bone marrow stromal cells, undergoing induced osteogenic or adipogenic differentiation. Profiling of estrogen receptors (ERs)-alpha, -beta1, -beta2, -beta3, -beta4, -beta5, and aromatase mRNAs revealed lineage-dependent expression patterns. During osteogenic differentiation, the osteoblast-determining core binding factor-alpha1 showed a progressive increase, whereas the adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma) 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-kappaB ligand gene expression ratio, and the expression of TGFbeta1. During adipogenic differentiation, down-regulation in the mRNA levels of PPARgamma and CCAAT/enhancer-binding protein-alpha 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, TGFbeta1 was strongly up-regulated by genistein in an ER-dependent manner. Blocking the TGFbeta1 pathway abolished the effects of genistein on PPARgamma 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 17beta-estradiol) via an ER-dependent mechanism involving autocrine or paracrine TGFbeta1 signaling.

17β-Estradiol inhibition of PPARγ-induced adipogenesis and adipocyte-specific gene expression

“…However, E treatment prevented this troglitazone-induced lipid accumulation, indicating that E has an inhibitory effect on troglitazoneinduced adipogenesis. Similarly, adipogenic differentiation and maturation are reported to be reduced by E and genistein via an ER-dependent mechanism [18][19][20] . PPARγ transcriptional activity and its effects on adipogenic differentiation were enhanced in the absence of E, whereas E inhibited PPARγ-mediated adipocyte differentiation [18,28] .…”

“…Consistent with the effects of E on troglitazone-induced adipogenesis, E decreased the expression of PPARγ and the PPARγ target genes aP2 and LPL, which are directly implicated in lipogenic pathways, in both WAT of OVX mice and in 3T3-L1 adipocytes. Previous studies reported that E and genistein may have anti-lipogenic and anti-adipogenic effects by downregulating the expression of adipocyte-specific genes, such as PPARγ, CCAAT/enhancer binding protein α, aP2, and LPL, in OVX mice, primary human adipocytes, and mouse and human bone marrow stromal cells [18][19][20]28] . Similarly, troglitazone did not affect PPARγ mRNA expression or adipocyte-specific gene expression in E-producing female mice.…”

“…E also plays an important role in regulating adipocyte differentiation and development. E represses adipogenic differentiation and maturation via an estrogen receptor (ER)-dependent mecha-www.chinaphar.com Jeong S et al Acta Pharmacologica Sinica npg nism in human and mouse bone marrow stromal cells [18,19] . The phytoestrogen genistein, which has high affinity for ERs, inhibits adipocyte differentiation, lipid accumulation, and the expression of adipocyte-specific genes in primary human adipocytes [20] .…”

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

“…Furthermore, genistein decreased the adipogenic differentiation and maturation of bone marrow stromal cells, and stimulated their differentiation into osteoblasts. 32 These differences have been explained by the genistein differential effects on ER and PPAR-g pathways. 14,28 Indeed, the genistein-enhanced osteogenesis of osteoprogenitor KS483 cells is ER-mediated, whereas the genisteinenhanced adipogenesis of osteoprogenitor KS483 cells and mouse-bone marrow cells is PPAR-g-mediated.…”

Adipose Tissue-Derived Stem Cells Treated with Estradiol Enhance Survival of Autologous Fat Transplants

“…However, ADSCs exhibit lower proliferation and differentiation activities compared to MSCs (De Ugarte et al 2003;Huang et al 2005), requiring further improvement in this area. Sexual steroid estrogens play a significant role in modulating the growth, differentiation and metabolism of many tissues and cells (Cooke and Naaz 2004;Dang and Lowik 2004;Heim et al 2004;Talwar et al 2006). Among them, 17-β estradiol (E2) has been proved to be effective in promoting osteogenesis and adipogenesis of human bone marrow MSCs and to enhance vascular endothelial growth factor (VEGF) production due to the binding between E2 and estrogen receptors (ERs) (Hong et al 2006).…”