title: Simvastatin modulates mouse embryonic stem cell-derived chondrogenesis in vitro.
abstract: It has been studied in detail that cellular differentiation during chondrogenesis can be recapitulated in vitro by differentiation of embryonic stem (ES) cells as embryoid bodies (EBs). We here used this model system of cartilage development to analyze the effect of simvastatin, a potentially embryotoxic substance. Statins are a group of drugs used to treat hypercholesterolaemia. We found that simvastatin activated cartilage nodule formation during EB differentiation. Extended application of simvastatin resulted in enhanced expression of cartilage marker molecules and prolonged persistence of cartilage nodules. Expression of collagen type II was upregulated during simvastatin-induced chondrogenic ES cell differentiation as demonstrated by quantitative real time PCR. However, immunostaining for cartilage marker molecules revealed that cartilage nodules within simvastatin-treated EBs were defective, bearing cavities of cell loss. Furthermore, caspase activity was reduced in comparison to untreated controls indicating reduced apoptosis. Taken together, we may speculate that simvastatin prolongs survival of chondrocytes and disrupts cellular integrity of cartilage nodules during EB development by affecting apoptotic mechanisms. The study underlines that ES cell-derived EBs are a useful in vitro model to screen substances for their embryotoxic and teratogenic potential.
authors: Medical Dept. I and Dept. of Virology and Cell Biology, University of Lübeck, 23538 Lübeck, Germany. Jan_Kramer@gmx.de
authors: J
authors: J
authors: Kramer
authors: M
authors: M
authors: Bartsch
authors: D
authors: D
authors: Krug
authors: M
authors: M
authors: Klinger
authors: M
authors: M
authors: Nitschke
authors: J
authors: J
authors: Rohwedel
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000826:Animal Testing Alternatives; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis / Q000187:drug effects* / Q000502:physiology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D058732:Embryoid Bodies / Q000187:drug effects / Q000473:pathology; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000633:toxicity*; D051379:Mice; D019821:Simvastatin / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053674:Aggrecans; D015415:Biomarkers; D024043:Collagen Type II; D000960:Hypolipidemic Agents; D019821:Simvastatin