Book ChapterDOI
The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics.
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TLDR
Calcilytics are being evaluated as a means of inducing a "pulse" in the circulating parathyroid hormone (PTH) concentration, which would mimic that resulting from injection of PTH, an established anabolic form of treatment for osteoporosis.Abstract:
The extracellular calcium (Ca2+_o)-sensing receptor (CaR) enables the parathyroid glands and other CaR-expressing cells to sense alterations in the level of Ca2+_o and to respond with changes in function that are directed at normalizing the blood calcium concentration In addition to the parathyroid gland, the kidney is a key site for Ca2+_o-sensing that enables it to make physiologically relevant alterations in divalent cation and water metabolism Several disorders of Ca2+_o-sensing arise from inherited or acquired abnormalities that “reset” the serum calcium concentration upward or downward Inactivating mutations produce a benign form of hypercalcemia when present in the heterozygous state, termed Familial Hypocalciuric Hypercalcemia (FHH), while homozygous mutations produce a much more severe hypercalcemic disorder resulting from marked hyperparathyroidism, called Neonatal Severe Hyperparathyroidism (NSHPT) Activating mutations cause a hypocalcemic syndrome of varying severity, termed autosomal dominant hypocalcemia or hypoparathyroidism Inactivating or activating antibodies directed at the CaR produce the expected hyper- or hypocalcemic syndromes, respectively “Calcimimetic” CaR activators and “calcilytic” CaR antagonists have been developed The calcimimetics are currently in use for controlling severe hyperparathyroidism in patients receiving dialysis treatment for end stage renal disease or with parathyroid cancer Calcilytics are being evaluated as a means of inducing a “pulse” in the circulating parathyroid hormone (PTH) concentration, which would mimic that resulting from injection of PTH, an established anabolic form of treatment for osteoporosisread more
Citations
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Journal ArticleDOI
Osteoporosis: now and the future
TL;DR: Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation and the most promising novel treatments include denosumab, a monoclonal antibody for receptor activator of NF-κB ligand; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation.
Journal ArticleDOI
Calcium Metabolism in Health and Disease
TL;DR: Increasing evidence suggests that calcium supplementation may enhance soft tissue calcification and cardiovascular disease in CKD-MBD, and further research is needed to elucidate the risks and mechanisms of soft tissues calcification with calcium supplementation in both healthy subjects and patients with chronic kidney disease.
Calcimimetics with potent and selective activity on the parathyroid calcium receptor (cytoplasmic Ca21yhyperparathyroidismyparathyroid cellsyNPS R-568yNPS R-467)
Edward F. Nemeth,Michael E. Steffey,L Ance G. Hammerland,C. P. Hung,Bradford C. Van Wagenen,E Ric G. Delmar,Manuel F. Balandrin +6 more
TL;DR: In this paper, phenylalkylamine com-pounds, typified by NPS R-568 and its deschloro derivative NPSR-467, increased the concentration of cytoplasmic Ca 2 1 ([Ca 2 1 ] i ) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations.
Journal ArticleDOI
Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery
TL;DR: This review addresses the current knowledge regarding maternal adaptations in mineral and skeletal homeostasis that occur during pregnancy, lactation, and post-weaning recovery and the impacts that these adaptations have on biochemical and hormonal parameters of mineralHomeostasis.
Journal ArticleDOI
The Extracellular Calcium-Sensing Receptor (CaSR) Is a Critical Modulator of Skeletal Development
TL;DR: A critical role is shown for the CaSR in early embryogenesis and skeletal development and an alternatively spliced form of the receptor that provides at least partial compensation for loss of the full-length receptor is developed.
References
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Journal ArticleDOI
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.
Robert M. Neer,Claude D. Arnaud,Jose R. Zanchetta,Richard L. Prince,Gregory A Gaich,Jean-Yves Reginster,Anthony B. Hodsman,Erik Fink Eriksen,Sophia Ish-Shalom,Harry K. Genant,Ouhong Wang,Bruce H. Mitlak +11 more
TL;DR: Treatment of postmenopausal osteoporosis with parathyroid hormone decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated.
Journal ArticleDOI
Cloning and characterization of an extracellular Ca 2+ -sensing receptor from bovine parathyroid
Edward M. Brown,Gerardo Gamba,Daniela Riccardi,Michael Lombardi,Robert Butters,Olga Kifor,Adam Sun,Adam Sun,Matthias A. Hediger,Jonathan Lytton,Steven C. Hebert +10 more
TL;DR: The cloning of complementary DNA encoding an extracellular Ca2+ -sensing receptor from bovine parathyroid is reported with pharmacological and functional properties nearly identical to those of the native receptor.
Journal ArticleDOI
Extracellular Calcium Sensing and Extracellular Calcium Signaling
Edward M. Brown,R. John MacLeod +1 more
TL;DR: The cloning of a G protein-coupled extracellular Ca(2+) (Ca(o)(2+))-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca( o)(2+) on tissues that maintain systemic Ca(o](2+) homeostasis, especially parathyroid chief cells and several cells in the kidney.
Journal ArticleDOI
Cinacalcet for Secondary Hyperparathyroidism in Patients Receiving Hemodialysis
Geoffrey A. Block,Kevin J. Martin,Angel L.M. de Francisco,Stewart A. Turner,Morrell M. Avram,Michael Suranyi,Gavril Hercz,John Cunningham,Ali K. Abu-Alfa,Piergiorgio Messa,Daniel W. Coyne,Francesco Locatelli,Raphael M. Cohen,Pieter Evenepoel,Sharon M. Moe,Albert Fournier,Johann Braun,Laura C. McCary,Valter J. Zani,Kurt Olson,Tilman B. Drüeke,William G. Goodman +21 more
TL;DR: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.
Journal ArticleDOI
Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism
Martin R. Pollak,Edward M. Brown,Yah-Huei Wu Chou,Steven C. Hebert,Stephen J. Marx,Beat Stelnmann,Tatjana Levi,Christine E. Seidman,Jon G. Seidman +8 more
TL;DR: It is demonstrated that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis.
Related Papers (5)
Extracellular Calcium Sensing and Extracellular Calcium Signaling
Edward M. Brown,R. John MacLeod +1 more