Mineralocorticoid receptor function in bone metabolism and its role in glucocorticoid-induced osteopenia

Fumoto, Toshio; Ishii, Kiyo aki; Ito, Masako; Berger, Stefan; Schütz, Günther; Ikeda, Kyoji

doi:10.1016/j.bbrc.2014.03.149

Cited by 34 publications

(32 citation statements)

References 28 publications

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“…Among the TF only the NR3C2 (mineralocorticoid receptor) was estimated by IPA to be induced during osteogenesis. The NR3C2 has been previously reported to be involved in osteoblast differentiation [ 88 ] but very recently it has been demonstrated to have a negative effect on bone formation by the same nuclear receptor [ 89 ]. SREBP2 is a master regulator of cholesterol synthesis [ 90 ] and the inhibition of this TF supported the inhibition of sterol synthesis indicated by the DIA analysis ( Fig 3 ).…”

Section: Resultsmentioning

confidence: 99%

Transcription Adaptation during In Vitro Adipogenesis and Osteogenesis of Porcine Mesenchymal Stem Cells: Dynamics of Pathways, Biological Processes, Up-Stream Regulators, and Gene Networks

2015

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The importance of mesenchymal stem cells (MSC) for bone regeneration is growing. Among MSC the bone marrow-derived stem cells (BMSC) are considered the gold standard in tissue engineering and regenerative medicine; however, the adipose-derived stem cells (ASC) have very similar properties and some advantages to be considered a good alternative to BMSC. The molecular mechanisms driving adipogenesis are relatively well-known but mechanisms driving osteogenesis are poorly known, particularly in pig. In the present study we have used transcriptome analysis to unravel pathways and biological functions driving in vitro adipogenesis and osteogenesis in BMSC and ASC. The analysis was performed using the novel Dynamic Impact Approach and functional enrichment analysis. In addition, a k-mean cluster analysis in association with enrichment analysis, networks reconstruction, and transcription factors overlapping analysis were performed in order to uncover the coordination of biological functions underlining differentiations. Analysis indicated a larger and more coordinated transcriptomic adaptation during adipogenesis compared to osteogenesis, with a larger induction of metabolism, particularly lipid synthesis (mostly triglycerides), and a larger use of amino acids for synthesis of feed-forward adipogenic compounds, larger cell signaling, lower cell-to-cell interactions, particularly for the cytoskeleton organization and cell junctions, and lower cell proliferation. The coordination of adipogenesis was mostly driven by Peroxisome Proliferator-activated Receptors together with other known adipogenic transcription factors. Only a few pathways and functions were more induced during osteogenesis compared to adipogenesis and some were more inhibited during osteogenesis, such as cholesterol and protein synthesis. Up-stream transcription factor analysis indicated activation of several lipid-related transcription regulators (e.g., PPARs and CEBPα) during adipogenesis but osteogenesis was driven by inhibition of several up-stream regulators, such as MYC. Between MSCs the data indicated an ‘adipocyte memory’ in ASC with also an apparent lower immunogenicity compared to BMSC during differentiations. Overall the analysis allowed proposing a dynamic model for the adipogenic and osteogenic differentiation in porcine ASC and BMSC.

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Section: Resultsmentioning

confidence: 99%

Transcription Adaptation during In Vitro Adipogenesis and Osteogenesis of Porcine Mesenchymal Stem Cells: Dynamics of Pathways, Biological Processes, Up-Stream Regulators, and Gene Networks

2015

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“…It is interesting to note that the recent genome wide association study, aimed at identifying new candidate genes for bone strength, showed a strong association between phenotypes of bone strength and genes belonging to the mineralocorticoid pathway (10). In this regard, it should be mentioned that the expression of mineralocorticoid receptors on bone cells (11,12) could actually suggest a still unknown direct effect of mineralocorticoids on the skeletal tissue. Indeed, in an animal model, Fumoto et al showed that pharmacological inhibition of mineralocorticoid function with eplerenone resulted in increased bone mass, with stimulation of bone formation and suppression of resorption (12).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, it should be mentioned that the expression of mineralocorticoid receptors on bone cells (11,12) could actually suggest a still unknown direct effect of mineralocorticoids on the skeletal tissue. Indeed, in an animal model, Fumoto et al showed that pharmacological inhibition of mineralocorticoid function with eplerenone resulted in increased bone mass, with stimulation of bone formation and suppression of resorption (12). The treatment with eplerenone as well as the specific deletion of mineralocorticoid receptor in osteocytes improved the cortical bone thinning in the prednisolonetreated mouse (12).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in an animal model, Fumoto et al showed that pharmacological inhibition of mineralocorticoid function with eplerenone resulted in increased bone mass, with stimulation of bone formation and suppression of resorption (12). The treatment with eplerenone as well as the specific deletion of mineralocorticoid receptor in osteocytes improved the cortical bone thinning in the prednisolonetreated mouse (12).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the possible relation between PA and bone was suggested by data coming from genomewide association studies showing an association between indexes of bone strength and some genes involved in aldosterone pathways (10). Finally, the presence of mineralocorticoid receptors had been demonstrated in osteoblast, osteoclast and osteocyte cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

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