Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health
Clinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcif...
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MDPI AG
2023-10-01
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| author | Claudia Bruedigam Johannes P. T. M. van Leeuwen Jeroen van de Peppel |
| author_facet | Claudia Bruedigam Johannes P. T. M. van Leeuwen Jeroen van de Peppel |
| author_sort | Claudia Bruedigam |
| collection | DOAJ |
| description | Clinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect diminished by the antioxidant resveratrol. Here, we aimed to elucidate transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype. We performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48 h during the first two days of differentiation, a phase that we show is sufficient for rosiglitazone stimulation of mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained well-known primary PPAR targets and was also endogenously regulated during osteogenic hMSC differentiation and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets to be differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their non-mineralizing counterparts. These targets, i.e., PDK4, SDC4, SPRY4, TCF4 and DACT1, may specifically control extracellular matrix mineralization in vascular cells, and hence provide target candidates for further investigations to improve vascular health. |
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| language | English |
| last_indexed | 2024-03-10T21:22:02Z |
| publishDate | 2023-10-01 |
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| series | Cells |
| spelling | doaj.art-deb07e36d9554006a4669af259995c662023-11-19T16:02:29ZengMDPI AGCells2073-44092023-10-011220246210.3390/cells12202462Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular HealthClaudia Bruedigam0Johannes P. T. M. van Leeuwen1Jeroen van de Peppel2Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The NetherlandsDepartment of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The NetherlandsDepartment of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The NetherlandsClinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect diminished by the antioxidant resveratrol. Here, we aimed to elucidate transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype. We performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48 h during the first two days of differentiation, a phase that we show is sufficient for rosiglitazone stimulation of mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained well-known primary PPAR targets and was also endogenously regulated during osteogenic hMSC differentiation and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets to be differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their non-mineralizing counterparts. These targets, i.e., PDK4, SDC4, SPRY4, TCF4 and DACT1, may specifically control extracellular matrix mineralization in vascular cells, and hence provide target candidates for further investigations to improve vascular health.https://www.mdpi.com/2073-4409/12/20/2462osteoblastsmesenchymal stem cellsvascular smooth musclerosiglitazonePPAR-gammavascular calcification |
| spellingShingle | Claudia Bruedigam Johannes P. T. M. van Leeuwen Jeroen van de Peppel Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health Cells osteoblasts mesenchymal stem cells vascular smooth muscle rosiglitazone PPAR-gamma vascular calcification |
| title | Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health |
| title_full | Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health |
| title_fullStr | Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health |
| title_full_unstemmed | Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health |
| title_short | Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health |
| title_sort | gene expression analyses in models of rosiglitazone induced physiological and pathological mineralization identify novel targets to improve bone and vascular health |
| topic | osteoblasts mesenchymal stem cells vascular smooth muscle rosiglitazone PPAR-gamma vascular calcification |
| url | https://www.mdpi.com/2073-4409/12/20/2462 |
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