Abstract
BackgroundPatients 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.MethodsIn 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.ResultsOur 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.ConclusionsThe 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.
Highlights
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 cell (hMSC) that are able to differentiate into osteoblasts, leading to suppressed osteogenesis [2, 3]
transforming growth factor beta (TGFβ) induces hMSCs to switch from adipogenic to osteogenic differentiation bone morphogenetic protein (BMP) have been described as positive regulators of both osteogenesis and adipogenesis [8, 10]
In order to study the effect of BMP2 on differentiation of hMSCs in more detail, we cultured these cells in either osteogenic differentiation medium or adipogenic differentiation medium in the absence and presence of BMP2
Summary
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, leading to suppressed osteogenesis. Most information about the signaling pathways that are required for osteogenic and adipogenic differentiation of hMSCs has come from in-vitro studies, whereby cells are treated with specific combinations of growth factors and hormones [7]. Differentiation into both lineages requires treatment of monolayer cells with dexamethasone (DEX) and is enhanced by the presence of bone morphogenetic proteins (BMPs). Our previous data have indicated that under these experimental conditions at least 75 % of the hMSCs differentiate into either osteoblasts or adipocytes [7]
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