The calcium-sensing receptor in bone cells: a potential therapeutic target in osteoporosis.

Clinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR).

More than 200 naturally occurring mutations have been identified in the human CaSR, which have been linked to diseases involving dysregulation of extracellular Ca2+ homeostasis. These mutations have classically been termed “loss-” or “gain-of-function” mutations, which is an oversimplification given that amino acid changes can alter numerous molecular properties of a receptor. We thus sought to characterize the effects of 21 clinically relevant mutations, the majority located in the heptahelical domains and extracellular loop regions of the CaSR, using flow cytometry to measure cell surface receptor expression levels, and measurements of intracellular Ca2+ mobilization and ERK1/2 phosphorylation to monitor receptor signaling. We identified distinct molecular phenotypes caused by these naturally occurring amino acid substitutions, which included combinations of loss- and gain-of-expression and changes in intrinsic signaling capacity. Importantly, we also identified biased signaling in the response of the C...

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Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor

Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis. Bone, in major part, responds to calcium-dependent signals from the parathyroids and via vitamin D metabolites, although bone retains direct response to extracellular calcium if parathyroid regulation is lost. Improved understanding of calcium transporters and calcium-regulated cellular processes has resulted from analysis of genetic defects, including several defects with low or high bone mass. Osteoblasts deposit calcium by mechanisms including phosphate and calcium transport with alkalinization to absorb acid created by mineral deposition; cartilage calcium mineralization occurs by passive diffusion and phosphate production. Calcium mobilization by osteoclasts is mediated by acid secretion. Both bone forming and bone resorbing cells use calcium signals as regulators of differentiation and activity. This has been studied in more detail in osteoclasts, where both osteoclast differentiation and motility are regulated by calcium.

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Calcium and bone disease.

The calcium-sensing receptor (CaSR) regulates organismal Ca2+ homeostasis. Dysregulation of CaSR expression or mutations in the CASR gene cause disorders of Ca2+ homeostasis and contribute to the progression or severity of cancers and cardiovascular disease. This brief review highlights recent findings that define the CaSR life cycle, which controls the cellular abundance of CaSR and CaSR signaling. A novel mechanism, termed agonist-driven insertional signaling (ADIS), contributes to the unique hallmarks of CaSR signaling, including the high degree of cooperativity and the lack of functional desensitization. Agonist-mediated activation of plasma membrane-localized CaSR increases the rate of insertion of CaSR at the plasma membrane without altering the constitutive endocytosis rate, thereby acutely increasing the maximum signaling response. Prolonged CaSR signaling requires a large intracellular ADIS-mobilizable pool of CaSR, which is maintained by signaling-mediated increases in biosynthesis. This model p...

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Minireview: the intimate link between calcium sensing receptor trafficking and signaling: implications for disorders of calcium homeostasis.

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.

T A Theman

Papers

The role of the calcium-sensing receptor in bone biology and pathophysiology.