Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFβ-mediated signaling

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.

Do GPs and psychiatrists recommend alternatives when prescribing anti-depressants?

This study explores whether a partial explanation for high antidepressant prescription rates is the failure of prescribers to recommend alternatives. 1,829 New Zealand adults were asked which of six non-pharmacological treatment approaches were recommended when prescribed anti-depressants. The majority (82%) received at least one recommendation and 32% received three or more, most commonly ‘Counsellor/Psychologist/Psychotherapist’ (74%) and Exercise Schedule (43%). It cannot, therefore, be concluded that failing to consider non-pharmacological treatments is a major cause of high prescribing rates. Being younger and more severely depressed were both positively related to number of recommendations. Psychiatrists made significantly more recommendations than GPs.