title: TGFβ-induced switch from adipogenic to osteogenic differentiation of human mesenchymal stem cells: identification of drug targets for prevention of fat cell differentiation.
abstract: Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis.
  
  
  
  In order to be able to interfere with this process, we have investigated in-vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation.
  
  
  
  Our data show that BMP2 promotes both adipogenic and osteogenic differentiation of hMSCs, while transforming growth factor beta (TGFβ) inhibits differentiation into both lineages. However, when cells are cultured under adipogenic differentiation conditions, which contain cAMP-enhancing agents such as IBMX of PGE2, TGFβ promotes osteogenic differentiation, while at the same time inhibiting adipogenic differentiation. Gene expression and immunoblot analysis indicated that IBMX-induced suppression of HDAC5 levels plays an important role in the inhibitory effect of TGFβ on osteogenic differentiation. By means of gene expression microarray analysis, we have investigated genes which are downregulated by TGFβ under adipogenic differentiation conditions and may therefore be potential targets for prevention of fat cell differentiation. We thus identified nine genes for which FDA-approved drugs are available. Our results show that drugs directed against the nuclear hormone receptor PPARG, the metalloproteinase ADAMTS5, and the aldo-keto reductase AKR1B10 inhibit adipogenic differentiation in a dose-dependent manner, although in contrast to TGFβ they do not appear to promote osteogenic differentiation.
  
  
  
  The approach chosen in this study has resulted in the identification of new targets for inhibition of fat cell differentiation, which may not only be relevant for prevention of osteoporosis, but also of obesity.
authors: Department of Cell and Applied Biology, Faculty of Science, Radboud University Nijmegen, PO Box 9010, 6500 GL, Nijmegen, The Netherlands. jovazo@wxs.nl.|Present Address: Department of Cell and Applied Biology, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands. jovazo@wxs.nl.
authors: Everardus J
authors: EJ
authors: van Zoelen
authors: Department of Cell and Applied Biology, Faculty of Science, Radboud University Nijmegen, PO Box 9010, 6500 GL, Nijmegen, The Netherlands.|Present Address: Department of Cell and Applied Biology, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.|Present Address: Systems Biology and Bioinformatics Laboratory (SysBioLab), University of Algarve, Faro, Portugal.
authors: Isabel
authors: I
authors: Duarte
authors: Department of Cell and Applied Biology, Faculty of Science, Radboud University Nijmegen, PO Box 9010, 6500 GL, Nijmegen, The Netherlands.|Present Address: Department of Cell and Applied Biology, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.|Present Address: Department of Physical Organic Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors: José M
authors: JM
authors: Hendriks
authors: Department of Cell and Applied Biology, Faculty of Science, Radboud University Nijmegen, PO Box 9010, 6500 GL, Nijmegen, The Netherlands.|Present Address: Department of Cell and Applied Biology, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.|Present Address: ARGENX BVBA, Technologiepark 30, B-9052, Zwijnaarde, Belgium.
authors: Sebastian P
authors: SP
authors: van der Woning
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000378:metabolism / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D006655:Histone Deacetylases; D015232:Dinoprostone
keywords: Adipogenesis; Aldo-keto reductase; Bone marrow; Histone deacetylase; Mesenchymal stem cell; Metalloproteinase; Osteogenesis; Osteoporosis