Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

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.

Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology

“…2d and e). These data are important as a dramatically blunted snout is prevalent at a relatively early age in IDUA −/− mice (12 weeks) (Clarke et al 1997) as well as are in agreement with another murine model with losartan that showed beneficial effects to the skeleton (Chen et al 2015). …”

C-Raf promotes Angiogenesis during Normal Growth Plate Maturation

“…The initiation of VEGF translation is enhanced by angiotensin II in an Akt-dependent manner (Feliers et al, 2005). Consistent with this, treatment of mice with an angiotensin receptor blocker leads to expansion of the hypertrophic chondrocyte zone of the growth plate (Chen et al, 2015a). However, c-Raf ablation did not alter p-Akt levels in cultured chondrocytes (Fig.…”

The Effects of Losartan on Lipid Peroxidation and the Antioxidant System in the Bone Tissue of Diabetic Rats

“…AT1 reseptörünün losartan ile blokajının anti-inflamatuvar ve anti-osteoklastik etkiler gösterdiği böylelikle alveolar kemik kaybını önlediği gösterilmiştir (48). Anjiyotensin yolağının losartan aracılı inhibisyonu ile kemik kütlesinin arttığı ve iskelet gelişimi sırasında büyüme plakasında kondrosit hipertrofisini hızlandırdığı gösterilmiştir (49). Daha önce yapılan bir çalışmada renal hasarlanmada losartan tedavisinin TBARS seviyelerini düşürdüğü ve KAT aktivitesinde artışı tetiklediği gösterilmiştir (44).…”