title: 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.
authors.affiliation: Department of Biostatistics, University of Texas Health Science Center at Houston School of Public Health.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Grover
authors.affiliation: Boston University School of Medicine Orthopedic Surgery, Boston University, Boston, MA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Sibai
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston, TX, USA.
authors.forename: Nahid
authors.initials: N
authors.lastname: Rianon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Abbhirami
authors.initials: A
authors.lastname: Rajagopal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Laboratory of Skeletal Biology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Bae
mesh_terms: D000809:Angiotensins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000648:ultrastructure; D002356:Cartilage / Q000187:drug effects; D002454:Cell Differentiation; D019902:Chondrocytes / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006132:Growth Plate / Q000187:drug effects; D006984:Hypertrophy / Q000209:etiology; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067996:RAW 264.7 Cells; D011859:Radiography
chemical_list: D000809:Angiotensins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan
keywords: ARB; Chondrocyte; ERK phosphorylation; Losartan; Osteoclasts; RANKL