The calcium-sensing receptor mediates bone turnover induced by dietary calcium and parathyroid hormone in neonates

Abstract

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.

1,25-Dihydroxyvitamin D3 contributes to regulating mammary calcium transport and modulates neonatal skeletal growth and turnover cooperatively with calcium

“…Our results examining TRAP-positive osteoclast numbers and surface in the 2-wk-old pups with varying levels of calcium and 1,25(OH) 2 D 3 suggest that the absence of the bone-resorbing activity of 1,25(OH) 2 D 3 may supersede any effect of calcium on bone resorption, and in fact calcium supplementation in the 2-wk-old mice may inhibit osteoclastic bone resorption, as we reported previously (38), either directly (22), indirectly, or both. Thus, calcitonin release in rodents has been implicated in bone sparing in lactating females (43) and could help explain the reduced osteoclasts in the pups with elevations in calcium.…”

“…More recent studies have reported that deletion of the Casr gene in osteoblasts profoundly blocked postnatal growth and skeletal development, a finding that was evident by 3 days of age (5). Our recent study has demonstrated that CaR deficiency abolishes skeletal responses to dietary calcium supplementation in suckling neonates (38) and suggests that raising serum calcium concentration by dietary calcium supplementation may activate CaR and subsequently produce a skeletal anabolic action, at least in the neonates. Taken together, these data suggest that 1,25(OH) 2 D 3 and calcium can each exert cooperative roles on osteoblastic bone formation in the neonate.…”

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

“…Moreover, since bone formation is increased in the CaSR−/−, probably because of hyperparathyroidism, reduced in the PTH−/−, and markedly reduced in the CaSR−/−PTH−/−, it can be inferred that CaSR plays a stimulatory effect on osteoblast function, as observed in previous cell culture experiments [11,19]. Additional studies performed in wild-type, PTH−/− and CaSR−/ −PTH−/− pups fed a normal diet or high-calcium diet or treated with PTH have shown that CaSR is essential in mediating the alterations in bone turnover following changes in dietary calcium and the PTH-induced modifications in bone turnover [64].…”

The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice

“…Previously, we reported a skeletal anabolic effect for CaSR in neonates in association with daily exogenous PTH administration (43). These studies suggest a skeletal anabolic role for CaSR in the fetus and neonate independent of its role of maintaining calcium homeostasis in adult animals.…”

“…In contrast, mice with osteoblast-specific deletion of CaSR exhibit undermineralized skeletons (5). CaSR also mediates alterations in bone turnover in murine neonates in response to changes in dietary calcium and modulates PTH-stimulated bone turnover, which is required for bone anabolism (43). In adult mouse models we recently provided evidence that the absence of [Ca 2ϩ ] e -stimulated CaSR activity reduces bone resorption (37), and we (30) and others (11) have provided evidence in vivo in rodent models for the effect of an allosteric activator of CaSR, cinacalcet, to increase the number and activity of osteoclasts.…”