Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensins / drug effects
  • Angiotensins / metabolism
  • Animals
  • Bone Density / drug effects*
  • Bone Density / physiology
  • Bone Development / drug effects*
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / drug effects*
  • Bone and Bones / ultrastructure
  • Cartilage / drug effects
  • Cell Differentiation
  • Chondrocytes / drug effects*
  • Chondrocytes / physiology
  • Female
  • Growth Plate / drug effects
  • Hypertrophy / etiology
  • Losartan / administration & dosage
  • Losartan / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Osteoclasts / drug effects
  • Osteoclasts / physiology
  • Phosphorylation
  • RANK Ligand / antagonists & inhibitors
  • RANK Ligand / metabolism
  • RAW 264.7 Cells
  • Radiography

Substances

  • Angiotensins
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Losartan