The Calcium-Sensing Receptor Mediates Bone Turnover Induced by Dietary Calcium and Parathyroid Hormone in Neonates

We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)–induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth(–/–)) gene or of both Pth and CaR (Pth(–/–)CaR(–/–)) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1–34) (80 µg/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen–positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth(–/–) pups compared with WT pups and were decreased even more dramatically in Pth(–/–)CaR(–/–) pups. These parameters were increased in WT and Pth(–/–) pups but not in Pth(–/–)CaR(–/–) pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth(–/–), and Pth(–/–)CaR(–/–) pups following exogenous PTH treatment; however, the percentage increase was less in Pth(–/–)CaR(–/–) pups than in WT and Pth(–/–) pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth(–/–) pups and less significantly in Pth(–/–)CaR(–/–) pups compared with WT pups. These parameters were further reduced significantly in WT and Pth(–/–) pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth(–/–)CaR(–/–) pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH-stimulated bone turnover. © 2011 American Society for Bone and Mineral Research.