The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells
The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells
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DOI：
10.1210/en.2003-1014
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Bendik, I
中科院分区：
文献类型：
--
作者：
Heim, M;Frank, O;Bendik, I
在本研究中，我们研究了植物雌激素染料木黄酮和17 β-雌二醇在人骨髓基质细胞诱导成骨或成脂分化中的作用。雌激素受体（ER）-α，-β 1，-β 2，-β 3，-β 4，-β 5和芳香化酶mRNA的分析揭示了谱系依赖的表达模式。在成骨分化过程中，成骨细胞决定性核心结合因子-α 1呈进行性增加，而成脂调节剂过氧化物酶体增殖物激活受体γ（PPARgamma）依次减少。在早期成骨阶段，染料木黄酮强烈增强了这种谱系决定标记基因的时间调节。此外，染料木素增加碱性磷酸酶mRNA水平和活性，骨保护素：核因子-κ B配体基因表达的受体激活剂的比例，和TGF β 1的表达。在成脂分化过程中，在第3天观察到PPARgamma和CCAAT/增强子结合蛋白-α的mRNA水平下调，在第21天观察到脂蛋白脂酶和adipsin mRNA水平下降。这导致脂肪细胞数量减少，脂滴大小减少。在第3天的脂肪形成，TGF β 1强烈上调染料木素在ER依赖的方式。阻断TGF β 1通路消除了金雀异黄素对PPARgamma蛋白水平的影响，并导致前体细胞增殖率降低。总的来说，染料木黄酮增强骨髓基质细胞向成骨细胞谱系的承诺和分化，但不影响晚期成骨成熟标志物。另一方面，通过自分泌或旁分泌TGF β 1信号传导的ER依赖性机制，染料木素（和17 β-雌二醇）可降低脂肪分化和成熟。
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.