Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling
Querques, Francesca, Cantilena, Bruno, Cozzolino, Carmine, Esposito, M., Passaro, Fabiana, Parisi, Silvia, Lombardo, Barbara, Russo, Tommaso and Pastore, Lucio 2015. Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling. Journal of Cellular Physiology. 230 (7), pp. 1466-1474.
|Authors||Querques, Francesca, Cantilena, Bruno, Cozzolino, Carmine, Esposito, M., Passaro, Fabiana, Parisi, Silvia, Lombardo, Barbara, Russo, Tommaso and Pastore, Lucio|
Clinical studies of large human populations and pharmacological interventions in rodent models have recently suggested that anti-hypertensive drugs that target angiotensin II (Ang II) activity may also improve loss of bone mineral density. Here we identified in a genetic screen the Ang II type I receptor (AT1R) as a potential determinant of osteogenic differentiation and, implicitly, bone formation. Silencing of AT1R expression by RNA interference severely impaired the maturation of a multipotent mesenchymal cell line (W20-17) along the osteoblastic lineage. The same effect was also observed after the addition of the AT1R antagonist losartan but not the AT2R inhibitor PD123,319. Additional cell culture assays traced the time of greatest losartan action to the early stages of W20-17 differentiation, namely during cell proliferation. Indeed, addition of Ang II increased proliferation of differentiating W20-17 and primary mesenchymal stem cells and this stimulation was reversed by losartan treatment. Cells treated with losartan also displayed an appreciable decrease of activated (phosphorylated)-Smad2/3 proteins. Moreover, Ang II treatment elevated endogenous transforming growth factor β (TGFβ) expression considerably and in an AT1R-dependent manner. Finally, exogenous TGFβ was able to restore high proliferative activity to W20-17 cells that were treated with both Ang II and losartan. Collectively, these results suggest a novel mechanism of Ang II action in bone metabolism that is mediated by TGFβ and targets proliferation of osteoblast progenitors.
|Journal||Journal of Cellular Physiology|
|Journal citation||230 (7), pp. 1466-1474|
|Accepted author manuscript|
|Web address (URL)||http://dx.doi.org/10.1002/jcp.24887|
|27 Mar 2015|
|Publication process dates|
|Deposited||05 Jul 2016|
|Accepted||05 Dec 2014|
|Ministero dell'Istruzione dell'Università e della Ricerca|
|Copyright information||This is the peer reviewed version of the following article: Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling, 2015, Journal of Cellular Physiology, 230(7): 1466–1474, which has been published in final form at http://10.1002/jcp.24887. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.|
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