title: Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling.
abstract: 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.
authors.affiliation: CEINGE-Biotecnologie Avanzate, Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II,", Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Querques
authors.forename: Bruno
authors.initials: B
authors.lastname: Cantilena
authors.forename: Carmine
authors.initials: C
authors.lastname: Cozzolino
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Esposito
authors.forename: Fabiana
authors.initials: F
authors.lastname: Passaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Parisi
authors.forename: Barbara
authors.initials: B
authors.lastname: Lombardo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000809:Angiotensins; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D000809:Angiotensins; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; C073402:PD 123319; D019808:Losartan