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Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify
Claudia Bruedigam1, Johannes P T M van Leeuwen1, Jeroen van de Peppel1
1Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Abstract:
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.
Insights
Rosiglitazone accelerates vascular cell mineralization by altering gene expression. Five specific genes (PDK4, SDC4, SPRY4, TCF4, DACT1) were identified as potential targets for improving vascular health.
Area of Science:
- Biomedical Science
- Molecular Biology
- Vascular Biology
Background:
- The insulin sensitizer rosiglitazone has known detrimental skeletal and vascular effects.
- Previous work showed rosiglitazone accelerates osteoblast differentiation and vascular cell mineralization, with increased oxidative stress.
- Resveratrol, an antioxidant, can diminish rosiglitazone's pathological mineralization effect.
Purpose of the Study:
- To elucidate the transcriptional networks underlying rosiglitazone-enhanced vascular mineralization.
- To identify specific genes regulated by rosiglitazone in vascular cells and compare them to osteoblasts.
- To investigate potential therapeutic targets for improving vascular health by analyzing gene expression in vascular cells and patient carotid plaque.
Main Methods:
- Genome-wide transcriptional profiling (microarray) of osteogenic human mesenchymal stem cells (hMSCs) treated with rosiglitazone.
- Analysis of gene expression changes during early differentiation stages (1-48 hours).
- Comparative analysis of rosiglitazone targets in hMSCs, vascular smooth muscle cells (VSMCs) differentiating into calcifying vascular cells (CVCs), and patient carotid plaque data.
Main Results:
- Rosiglitazone treatment significantly altered the expression of 190 probes in osteogenic hMSCs.
- The identified rosiglitazone gene signature included known PPAR targets and genes regulated during osteogenic differentiation and VSMC to CVC differentiation.
- Five specific genes (PDK4, SDC4, SPRY4, TCF4, DACT1) were differentially regulated in CVCs and carotid plaque but not osteoblasts, suggesting a role in vascular mineralization.
Conclusions:
- Rosiglitazone induces pathological vascular mineralization through specific transcriptional changes.
- The identified genes PDK4, SDC4, SPRY4, TCF4, and DACT1 are potential key regulators of extracellular matrix mineralization in vascular cells.
- These genes represent promising therapeutic targets for interventions aimed at improving vascular health and preventing pathological calcification.
