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Physiological function of the angiotensin AT1a receptor in bone remodeling

✍ Scribed by Keiko Kaneko; Masako Ito; Toshio Fumoto; Ryoji Fukuhara; Junji Ishida; Akiyoshi Fukamizu; Kyoji Ikeda

Publisher
American Society for Bone and Mineral Research
Year
2011
Tongue
English
Weight
583 KB
Volume
26
Category
Article
ISSN
0884-0431

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✦ Synopsis

Abstract

In order to determine whether the renin‐angiotensin system (RAS) has any physiologic function in bone metabolism, mice lacking the gene encoding the major angiotensin II receptor isoform, AT1a, were studied using micro CT scanning, histomorphometric, and biochemical techniques. Three‐dimensional (3D) micro CT analysis of the tibial metaphysis revealed that both male and female AT1a knockout mice exhibited an increased trabecular bone volume along with increased trabecular number and connectivity. Histomorphometric analysis of the tibial metaphysis indicated that the parameters of bone formation as well as resorption were increased, which was also supported by elevated serum osteocalcin and carboxy‐terminal collagen crosslink (CTX) concentrations in the AT1a‐deficient mice. Osteoclastogenesis and osteoblastogenesis assays in ex vivo cultures, however, did not reveal any intrinsic alterations in the differentiation potential of AT1a‐deficient cells. Quantitative RT‐PCR using RNA isolated from the tibia and femur revealed that the receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) ratio and the expression of stromal cell‐derived factor (SDF)1α were increased, whereas that of SOST was decreased in AT1a‐deficient bone, which may account for the increased bone resorption and formation, respectively. AT1a‐deficient mice also displayed a lean phenotype with reduced serum leptin levels. They maintained high bone mass with advancing age, and were protected from bone loss induced by ovariectomy. Collectively, the data suggest that RAS has a physiologic function in bone remodeling, and that signaling through AT1a negatively regulates bone turnover and bone mass. © 2011 American Society for Bone and Mineral Research

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