The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells.
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.
Heim
M
M
Human Nutrition and Health, Research and Development, Roche Vitamins Ltd., VFHF, 205/219A, CH-4070 Basel, Switzerland.
Frank
O
O
Kampmann
G
G
Sochocky
N
N
Pennimpede
T
T
Fuchs
P
P
Hunziker
W
W
Weber
P
P
Martin
I
I
Bendik
I
I
D017667:Adipocytes / Q000166:cytology*; D000469:Alkaline Phosphatase / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology*; D002352:Carrier Proteins / Q000235:genetics; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D011416:Complement Factor D; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000235:genetics; D011960:Receptors, Estrogen / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics; D012794:Sialic Acids / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology*; D014157:Transcription Factors / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018124:Receptors, Tumor Necrosis Factor; C506895:SPP1 protein, human; D012794:Sialic Acids; D012795:Sialoglycoproteins; C508960:TGFB1 protein, human; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C038718:neural cell surface antigen BSP-2; D053495:Osteopontin; D004958:Estradiol; D019833:Genistein; D008071:Lipoprotein Lipase; D000469:Alkaline Phosphatase; D012697:Serine Endopeptidases; C493488:CFD protein, human; D011416:Complement Factor D