Angiotensin receptor blockers (ARBs) are a group of
anti-hypertensive drugs that are widely used to treat pediatric
hypertension. Recent application of ARBs to treat diseases such as
Marfan syndrome or
Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of
Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with
Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses.
Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level,
Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by
Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by
Losartan, suggesting a convergence of RANKL and
angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of
Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with
Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the
angiotensin pathway by
Losartan increases bone mass and accelerates chondrocyte
hypertrophy in growth plate during skeletal development.