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Sci. Signal., 2 September 2008
Vol. 1, Issue 35, p. ra1
[DOI: 10.1126/scisignal.1159945]


Editor's Summary

Bone Censor
The extracellular calcium-sensing receptor (CaSR) is a guanine nucleotide-binding protein (G protein)–coupled receptor (GPCR) that responds to changes in the concentration of extracellular calcium ([Ca2+]e) and modulates various functions of parathyroid cells (PTCs), chondrocytes (the cells that produce cartilage), osteoblasts, and renal tubular cells. Previous attempts to characterize the CaSR in Casr–/– mice have been hampered by the expression of an alternatively spliced form of the receptor that provides at least partial compensation for loss of the full-length receptor (see the Perspective by Brown and Lian). Chang et al. have now developed mice with cell type–specific knockout of Casr that do not express the alternative receptor. Mice with PTC- or osteoblast-specific deletion of Casr were viable but had postnatal skeletal defects. Unexpectedly, knockout of Casr in chondrocytes was lethal. Mice in which chondrocyte-specific knockout of Casr was induced late in embryonic life were viable but had delayed growth plate development. Together, these findings reveal a previously unappreciated role for the CaSR in embryonic and postnatal skeletal development.

Citation: W. Chang, C. Tu, T.-H. Chen, D. Bikle, D. Shoback, The Extracellular Calcium-Sensing Receptor (CaSR) Is a Critical Modulator of Skeletal Development. Sci. Signal. 1, ra1 (2008).

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Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human 'knockout'.
D. T. Ward, M. Z. Mughal, M. Ranieri, M. M. Dvorak-Ewell, G. Valenti, and D. Riccardi (2013)
Eur. J. Endocrinol. 169, K1-K7
   Abstract »    Full Text »    PDF »
Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo.
S. J. Quinn, A. R. B. Thomsen, J. L. Pang, L. Kantham, H. Brauner-Osborne, M. Pollak, D. Goltzman, and E. M. Brown (2013)
Am J Physiol Endocrinol Metab 304, E310-E320
   Abstract »    Full Text »    PDF »
Gastric Acid, Calcium Absorption, and Their Impact on Bone Health.
S. Kopic and J. P. Geibel (2013)
Physiol Rev 93, 189-268
   Abstract »    Full Text »    PDF »
Strontium Is a Biased Agonist of the Calcium-Sensing Receptor in Rat Medullary Thyroid Carcinoma 6-23 Cells.
A. R. B. Thomsen, J. Worm, S. E. Jacobsen, M. Stahlhut, M. Latta, and H. Brauner-Osborne (2012)
J. Pharmacol. Exp. Ther. 343, 638-649
   Abstract »    Full Text »    PDF »
Parathyroid Hormone-Independent Role for the Calcium-Sensing Receptor in the Control of Urinary Calcium Excretion.
D. Riccardi (2012)
J. Am. Soc. Nephrol. 23, 1766-1768
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The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice.
Y. Xue, Y. Xiao, J. Liu, A. C. Karaplis, M. R. Pollak, E. M. Brown, D. Miao, and D. Goltzman (2012)
Am J Physiol Endocrinol Metab 302, E841-E851
   Abstract »    Full Text »    PDF »
Successful Use of Bisphosphonate and Calcimimetic in Neonatal Severe Primary Hyperparathyroidism.
A. Wilhelm-Bals, P. Parvex, C. Magdelaine, and E. Girardin (2012)
Pediatrics 129, e812-e816
   Abstract »    Full Text »    PDF »
Negative Cross-talk between Calcium-sensing Receptor and {beta}-Catenin Signaling Systems in Colonic Epithelium.
O. Rey, W. Chang, D. Bikle, N. Rozengurt, S. H. Young, and E. Rozengurt (2012)
J. Biol. Chem. 287, 1158-1167
   Abstract »    Full Text »    PDF »
Mouse models for inherited endocrine and metabolic disorders.
S. E. Piret and R. V. Thakker (2011)
J. Endocrinol. 211, 211-230
   Abstract »    Full Text »    PDF »
1,25-Dihydroxyvitamin D3 contributes to regulating mammary calcium transport and modulates neonatal skeletal growth and turnover cooperatively with calcium.
J. Ji, R. Lu, X. Zhou, Y. Xue, C. Shi, D. Goltzman, and D. Miao (2011)
Am J Physiol Endocrinol Metab 301, E889-E900
   Abstract »    Full Text »    PDF »
Strontium Ranelate Decreases Receptor Activator of Nuclear Factor-{kappa}B Ligand-Induced Osteoclastic Differentiation In Vitro: Involvement of the Calcium-Sensing Receptor.
A. Caudrillier, A.-S. Hurtel-Lemaire, A. Wattel, F. Cournarie, C. Godin, L. Petit, J.-P. Petit, E. Terwilliger, S. Kamel, E. M. Brown, et al. (2010)
Mol. Pharmacol. 78, 569-576
   Abstract »    Full Text »    PDF »
Comparison of Active Vitamin D Compounds and a Calcimimetic in Mineral Homeostasis.
L. Nguyen-Yamamoto, I. Bolivar, S. A. Strugnell, and D. Goltzman (2010)
J. Am. Soc. Nephrol. 21, 1713-1723
   Abstract »    Full Text »    PDF »
Alterations in phosphorus, calcium and PTHrP contribute to defects in dental and dental alveolar bone formation in calcium-sensing receptor-deficient mice.
W. Sun, W. Sun, J. Liu, X. Zhou, Y. Xiao, A. Karaplis, M. R. Pollak, E. Brown, D. Goltzman, and D. Miao (2010)
Development 137, 985-992
   Abstract »    Full Text »    PDF »
Physiology and pathophysiology of the calcium-sensing receptor in the kidney.
D. Riccardi and E. M. Brown (2010)
Am J Physiol Renal Physiol 298, F485-F499
   Abstract »    Full Text »    PDF »
Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia.
B. Harding, M. C Lemos, A. A C Reed, G. V Walls, J. Jeyabalan, M. R Bowl, H. Tateossian, N. Sullivan, T. Hough, W. D Fraser, et al. (2009)
Endocr. Relat. Cancer 16, 1313-1327
   Abstract »    Full Text »    PDF »
Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications.
Z. Saidak, M. Brazier, S. Kamel, and R. Mentaverri (2009)
Mol. Pharmacol. 76, 1131-1144
   Abstract »    Full Text »    PDF »
The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion.
L. Kantham, S. J. Quinn, O. I. Egbuna, K. Baxi, R. Butters, J. L. Pang, M. R. Pollak, D. Goltzman, and E. M. Brown (2009)
Am J Physiol Endocrinol Metab 297, E915-E923
   Abstract »    Full Text »    PDF »
The full-length calcium-sensing receptor dampens the calcemic response to 1{alpha},25(OH)2 vitamin D3 in vivo independently of parathyroid hormone.
O. Egbuna, S. Quinn, L. Kantham, R. Butters, J. Pang, M. Pollak, D. Goltzman, and E. Brown (2009)
Am J Physiol Renal Physiol 297, F720-F728
   Abstract »    Full Text »    PDF »
No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions.
P. Wellendorph, L. D. Johansen, A. A Jensen, E. Casanova, M. Gassmann, P. Deprez, P. Clement-Lacroix, B. Bettler, and H. Brauner-Osborne (2009)
J. Mol. Endocrinol. 42, 215-223
   Abstract »    Full Text »    PDF »
New Insights in Bone Biology: Unmasking Skeletal Effects of the Extracellular Calcium-Sensing Receptor.
E. M. Brown and J. B. Lian (2008)
Science Signaling 1, pe40
   Abstract »    Full Text »    PDF »

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