title: Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling.
abstract: Recent evidence indicates that the vasculature contains mesenchymal stem cells (MSCs). We hypothesized that angiotensin II (Ang II) type 2 receptors (AT2Rs) play a role in the osteogenesis of MSCs and may have a role in vascular calcification. Human MSCs were differentiated into osteoblasts. Expression of AT2R was significantly increased during osteogenesis, whereas the expression of Ang II type 1 receptors was not significantly changed. Incubation with the AT2R blocker PD123319 with or without Ang II significantly inhibited calcium deposition, whereas type 1 receptor blocker valsartan had no significant effect. PD123319 inhibited extracellular signal-regulated kinase (ERK) phosphorylation in the osteogenic process, whereas valsartan had no effect. Furthermore, PD123319 combined with Ang II also inhibited acute ERK phosphorylation in MSCs induced by insulin. In conclusion, AT2R is upregulated during osteogenesis. Blockade of AT2R inhibits osteogenesis and ERK phosphorylation of human MSCs. These results provide a novel insight into the pathophysiology of calcific vascular disease.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA; Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Yaojiong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA; Institute of Medicine, Washington, DC, USA. Electronic address: victor.dzau@duke.edu.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D000068756:Valsartan / Q000494:pharmacology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; C073402:PD 123319; D000068756:Valsartan; D002118:Calcium
keywords: Calcification; osteoblast; osteogenesis; renin–angiotensin system