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During pregnancy, mineral concentrations, of calcium and phosphorus in particular, are maintained at a high level in fetal blood so that the developing skeleton may accrete adequate mineral content. The placenta actively transports minerals for this purpose. Maternal intestinal absorption increases in order to meet the fetal demand for calcium, which is only partly dependent on calcitriol. Mineral regulation is essentially dependent on parathyroid hormone (PTH) and PTH-related protein (PTHrP). The calcium-sensing receptor (CaSR) regulates PTH and PTHrP production. If calcium intake is insufficient, the maternal skeleton will undergo resorption due to PTHrP. After birth, a switch from fetal to neonatal homeostasis occurs through increase in PTH and calcitriol, and developmental adaptation of the kidneys and intestines with bone turnover contributing additional mineral to the circulation. Calcium absorption becomes progressively active and dependent on calcitriol. The postnatal skeleton can transiently present with osteoposis but adequate mineral diet usually allows full restoration. Cases of primary osteoporosis must be identified. Loss of trabecular mineral content occurs during lactation in order to provide calcium to the newborn. This programmed bone loss is dependent on a "brain-breast-bone" circuit. The physiological bone resorption during reproduction does not normally cause fractures or persistent osteoporosis. Women who experience fracture are likely to have other causes of bone loss., (Copyright © 2016. Published by Elsevier Masson SAS.)

Unlabelled: The calcium-sensing receptor (CaSR), a key player in the maintenance of calcium homeostasis, can influence bone modeling and remodeling by directly acting on bone cells, as demonstrated by in vivo and in vitro evidence. The modulation of CaSR signaling can play a role in bone anabolism., Introduction: The calcium-sensing receptor (CaSR) is a key player in the maintenance of calcium homeostasis through the regulation of PTH secretion and calcium homeostasis, thus indirectly influencing bone metabolism. In addition to this role, in vitro and in vivo evidence points to direct effects of CaSR in bone modeling and remodeling. In addition, the activation of the CaSR is one of the anabolic mechanisms implicated in the action of strontium ranelate, to reduce fracture risk., Methods: This review is based upon the acquisition of data from a PubMed enquiry using the terms "calcium sensing receptor," "CaSR" AND "bone remodeling," "bone modeling," "bone turnover," "osteoblast," "osteoclast," "osteocyte," "chondrocyte," "bone marrow," "calcilytics," "calcimimetics," "strontium," "osteoporosis," "skeletal homeostasis," and "bone metabolism.", Results: A fully functional CaSR is expressed in osteoblasts and osteoclasts, so that these cells are able to sense changes in the extracellular calcium and as a result modulate their behavior. CaSR agonists (calcimimetics) or antagonists (calcilytics) have the potential to indirectly influence skeletal homeostasis through the modulation of PTH secretion by the parathyroid glands. The bone anabolic effect of strontium ranelate, a divalent cation used as a treatment for postmenopausal and male osteoporosis, might be explained, at least in part, by the activation of CaSR in bone cells., Conclusions: Calcium released in the bone microenvironment during remodeling is a major factor in regulating bone cells. Osteoblast and osteoclast proliferation, differentiation, and apoptosis are influenced by local extracellular calcium concentration. Thus, the calcium-sensing properties of skeletal cells can be exploited in order to modulate bone turnover and can explain the bone anabolic effects of agents developed and employed to revert osteoporosis.

Maintaining a constant level of blood Ca(2+) is essential because of calcium's myriad intracellular and extracellular roles. The CaSR plays key roles in maintaining [Formula: see text] homeostasis by detecting small changes in blood Ca(2+) and modulating the production/secretion of the Ca(2+)-regulating hormones, PTH, CT, FGF23 and 1,25(OH)2D3, so as to appropriately regulate Ca(2+) transport into or out of blood via kidney, intestine, and/or bone. When Ca(2+) is high, the CaSR suppresses PTH synthesis and secretion, promotes its degradation, and inhibits parathyroid cellular proliferation. It has just the opposite effects on the C-cell, stimulating CT when [Formula: see text] is high. In bone, Ca(2+), acting via the CaSR, stimulates recruitment and proliferation of preosteoblasts, their differentiation to mature osteoblasts, and synthesis and mineralization of bone proteins. Conversely, [Formula: see text] inhibits the formation and activity and promotes apoptosis of osteoclasts, likely via the CaSR. These actions tend to mobilize skeletal Ca(2+) during [Formula: see text] deficiency and retain it when Ca(2+) is plentiful., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca(2+)). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We review the relevant mouse models and discuss the importance of CaR in chondrogenesis and osteogenesis. We present the evidence for a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations. Additionally, we review emerging research on the importance of the CaR to the regulation of serum calcium homeostasis independent of PTH, the role of the CaR in the hematopoietic stem cell niche with implications for bone marrow transplant, and early evidence that implies a role for the CaR as a factor in skeletal metastasis from breast and prostate cancer. We conclude with a discussion of drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), and the consequences for bone physiology and pathology.

The extracellular Ca(2+)-sensing receptor (CaSR) plays a nonredundant role in the functions of the parathyroid gland (PTG) and the kidney. Severe hyperparathyroidism, premature death, and incomplete gene excision in Casr(-/-) mice have precluded the assessment of CaSR function in other tissues. We generated mice with tissue-specific deletion of Casr in the PTG, bone, or cartilage. Deletion of Casr in the PTG or bone resulted in profound bone defects, whereas deletion of Casr in chondrocytes (cartilage-producing cells) resulted in death before embryonic day 13 (E13). Mice in which chondrocyte-specific deletion of Casr was induced between E16 and E18 were viable but showed delayed growth plate development. Our data show a critical role for the CaSR in early embryogenesis and skeletal development.

Experiments performed in mice in which expression of the extracellular calcium-sensing receptor (CaSR) was completely nullified specifically in parathyroid cells, chondrocytes, or cells of the osteoblast lineage have identified phenotypes that indicate a key role for the CaSR in embryonic development of the skeleton, postnatal bone formation, and osteoblast differentiation that are independent of the calcitropic hormone axis. These long-awaited studies further clarify the signaling relationships between the parathyroid gland, kidney, and metabolic bone disease in patients with mutations in the gene encoding the CaSR, and they provide new insights into understanding the signaling pathways involving the CaSR in skeletal cells.

Bone turnover helps accomplish long-term correction of the extracellular calcium (Ca2+ o) homeostasis by the actions of osteoblasts and osteoclasts. These processes are highly regulated by the actions of hormones, most prominently parathyroid hormone (PTH), the release of which is a function of the Ca2+ o, and is regulated by the action of the Ca2+ -sensing receptor (CaR) in the parathyroid gland. Various mutations of the CaR gene give rise to gain or loss of functions leading respectively to hypo- or hypercalcaemic conditions. CaR could conceivably be a target for local changes in the Ca2+ o in the bone microenvironment thereby acting as a 'growth factor' in various cells residing in the bone marrow. This review discusses about the roles of the CaR in bone. In osteoblasts, CaR promotes its proliferation, differentiation and mineralization. In osteoclasts, CaR mediates high Ca2+ o-stimulated osteoclast differentiation as well as osteoclast apoptosis. CaR regulates localization of haematopoietic stem cells from the foetal liver to endosteal niche, the socalled homing. Although the CaR plays a key role in the defense against hypercalcaemia, its function can be aberrant in humoral hypercalcaemia of malignancy in which CaR activation stimulates secretion of parathyroid hormone-related peptide (PTHrP) secretion. Increased levels of PTHrP cause a vicious hypercalcaemic state resulting from its increased bone-resorptive and positive renal calcium reabsorbing effects give rise to hypercalcaemia. CaR mediates a variety of functions of Ca2+ o in the bone microenvironment under both normal and pathological conditions.

In this article, we review the evidence that dietary protein has a positive influence on bone health, reduces hip fracture risk, and promotes postfracture recovery, and we consider the molecular, cellular, and endocrine bases of the interactions that link protein and calcium metabolism, including effects via IGF-1 and PTH. In addition, we consider the roles of amino acid-sensing mechanisms in coupling dietary protein intake to metabolic change as well as the central role of calcium-sensing receptors (CaRs) in the control of calcium metabolism. Finally, we consider how recently identified broad-spectrum amino acid-sensing receptors from class 3 of the G-protein coupled receptor superfamily including, remarkably, the CaR itself may contribute to the impact of dietary protein on bone.

Calcimimetics suppress parathyroid hormone (PTH) secretion by allosterically acting on parathyroid calcium-sensing receptor. It has been already shown that one of calcimimetics decreases PTH level, calcium-phosphate product and bone-specific alkaline phosphatase (BAP) in patients with secondary hyperparathyroidism (SHPT) caused by end-stage renal disease. It has been also described that this drug ameliorates osteitis fibrosa in uremic rats. However, there has been so far insufficient evidence showing that calcimimetics increase bone mineral density and decrease fractures in human. Effects of calcimimetics on bone metabolism need to be investigated by clinical studies for longer usage of this drug in the future.

Primary hyperparathyroidism is a disease in which somatic chromosomal defects such as activations of oncogenes or inactivations of tumor suppressor genes enhance chromosomal parathyroid cell growth. Decreased calcium-sensing receptor causes oversecretion of PTH from abnormal parathyroid cells. Oversecreted PTH enhances bone turnover and finally exhibits bone fragility. In this review, the indications of parathyroidectomy and the effects of parathyroidectomy on bone in primary hyperparathyroidism are discussed.

Changes in extracellular [Ca2+] modulate the function of bone cells in vitro via the extracellular Ca2+-sensing receptor (CaR). Within bone microenvironments, resorption increases extracellular [Ca2+] locally. To determine whether enhanced CaR signaling could modulate remodeling and thereby bone mass in vivo, we generated transgenic mice with a constitutively active mutant CaR (Act-CaR) targeted to their mature osteoblasts by the 3.5 kb osteocalcin promoter. Longitudinal microcomputed tomography of cancellous bone revealed reduced bone volume and density, accompanied by a diminished trabecular network, in the Act-CaR mice. The bone loss was secondary to an increased number and activity of osteoclasts, demonstrated by histomorphometry of secondary spongiosa. Histomorphometry, conversely, indicates that bone formation rates were unchanged in the transgenic mice. Constitutive signaling of the CaR in mature osteoblasts resulted in increased expression of RANK-L (receptor activator of nuclear factor-kappaB ligand), the major stimulator of osteoclast differentiation and activation, which is the likely underlying mechanism for the bone loss. The phenotype of Act-CaR mice is not attributable to systemic changes in serum [Ca2+] or PTH levels. We provide the first in vivo evidence that increased signaling by the CaR in mature osteoblasts can enhance bone resorption and further propose that fluctuations in the [Ca2+] within the bone microenvironment may modulate remodeling via the CaR.

Bone is the major sink and store for calcium and it fulfils essential roles in the maintenance of extracellular free ionised calcium concentration ([Ca2+]e) within its homeostatic range (1.1-1.3 mM). In response to acute hypercalcaemia or hypocalcaemia, Ca2+ is rapidly transported into or out of bone. Bone turnover (and therefore bone Ca2+ turnover) achieves the long-term correction of the [Ca2+]e by the metabolic actions of osteoblasts and osteoclasts, as they respectively incorporate or release Ca2+ from bone. These processes are regulated by the actions of hormones, such as parathyroid hormone (PTH), the release of which is a function of the [Ca2+]e, and is regulated by the action of the Ca2+-sensing receptor (CaR) in the parathyroid gland. Tissue culture studies indicate that bone cells also directly respond to increasing and decreasing [Ca2+]e in their vicinity, independently of the systemic factors. Nevertheless, further studies are necessary to identify how the acute and long-term local changes in [Ca2+]e affect bone cells and the physiological processes they are involved in. Also, the molecular mechanisms which enable the bone cells to sense and respond to [Ca2+]e are not clear. Like the parathyroid cells, bone cells also express the CaR, and accumulating evidence indicates the involvement of this receptor in their responses to the changing extracellular ionic environment.

The skeleton is a dynamic structure that undergoes continuous remodeling, a prerequisite to meeting the constant loading demands placed upon it. This process is controlled by a multitude of systemic and local factors which interact with receptors presented on the surface of both osteoblasts and osteoclasts; the osteogenic and osteolytic cells of bone. The seven transmembrane G-protein coupled superfamily of receptors are amongst the most important expressed by bone cells. Many local and systemic factors, including prostaglandins and parathyroid hormone, initiate cellular processes via interaction with members of this receptor family. The diversity of signals and signaling cross talk generated by activated G-protein receptor complexes, facilitates a huge range of downstream responses essential in the remodeling of the skeleton. Indeed, agonist-activated signaling crosstalk provides a mechanism for integrating the activities of local and systemic factors, an essential requirement of focal remodeling. This review has focused on those currently known seven transmembrane receptors expressed by bone cells that couple to G-proteins, and describes the nature of receptor-G protein interaction and the resultant functional consequences of effector activation within bone cells.