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Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ‐mediated signaling
Author(s) -
Querques Francesca,
Cantilena Bruno,
Cozzolino Carmine,
Esposito Maria Teresa,
Passaro Fabiana,
Parisi Silvia,
Lombardo Barbara,
Russo Tommaso,
Pastore Lucio
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24887
Subject(s) - losartan , angiotensin ii , progenitor cell , mesenchymal stem cell , cell growth , chemistry , microbiology and biotechnology , endocrinology , osteoblast , receptor , cancer research , cellular differentiation , pi3k/akt/mtor pathway , transforming growth factor , medicine , signal transduction , stem cell , biology , biochemistry , gene , in vitro
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 reduce loss of bone mineral density. Here, we identified in a genetic screening 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. J. Cell. Physiol. 230: 1466–1474, 2015. © 2015 Wiley Periodicals, Inc., A Wiley Company