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Mol Genet Metab. 2015 May;115(1):53-60. doi: 10.1016/j.ymgme.2015.02.006. Epub 2015 Feb 27.

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

Author information

1
Department of Biostatistics, University of Texas Health Science Center at Houston School of Public Health.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
3
Boston University School of Medicine Orthopedic Surgery, Boston University, Boston, MA, USA.
4
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
5
Department of Internal Medicine, University of Texas Medical School at Houston, TX, USA.
6
Laboratory of Skeletal Biology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Research Institute, Grand Rapids, MI, USA.
#
Contributed equally

Abstract

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.

KEYWORDS:

ARB; Chondrocyte; ERK phosphorylation; Losartan; Osteoclasts; RANKL

PMID:
25779879
PMCID:
PMC4426054
DOI:
10.1016/j.ymgme.2015.02.006
[Indexed for MEDLINE]
Free PMC Article

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