Advertisement
The hunting of the snark: the elusive calcium receptor(s)
Lawrence G. Raisz
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
Address correspondence to: Lawrence G. Raisz, University of Connecticut Health Center, Department of Medicine, General Clinical Research Center, MC3805, 263 Farmington Avenue, Farmington, Connecticut 06032, USA. Phone: (860) 679-3851; Fax: (860) 679-3209; E-mail: raisz@nso.uchc.edu.
Find articles by Raisz, L. in: JCI | PubMed | Google Scholar
Published April 1, 2003 - More info
J Clin Invest. 2003;111(7):945–947. https://doi.org/10.1172/JCI18235.
© 2003 The American Society for Clinical Investigation
“For the snark’s a peculiar creature that won’t be caught in a commonplace way.”
—Lewis Carroll, The Hunting of the Snark
The first hunt took a long time. The existence of a highly sensitive calcium-sensing receptor (CaSR) was postulated more than 30 years ago based on the exquisite ability of the parathyroid cell to respond to small changes in serum ionized calcium concentration (1). The gene encoding CaSR was finally cloned in 1993 (2). Shortly thereafter it was found that inactivating mutations in CaSR were responsible for familial hypocalciuric hypercalcemia (FHH) in heterozygotes and for severe hyperparathyroidism in homozygous infants while activating mutations caused hypoparathyroidism (3, 4). Deletion of the mouse calcium receptor mimics the phenotype of FHH in heterozygote individuals. In homozygous mice there is early death due to hypercalcemia and a surprising skeletal phenotype of rickets, which suggested that CaSR might be essential for normal mineralization (5, 6).
-
Double knockouts rescue the mice and their bones
In this issue of the JCI, two groups of investigators have developed ingenious double knockout models to permit CaSR-deficient mice to survive in an effort to define the potential importance of CaSR in mouse tissues other than the parathyroid glands. In the study by Kos et al. (14) the phenotype was rescued from hyperparathyroidism by the simple and direct approach of genetic ablation of the PTH gene itself. Quite a different strategy was used by Tu et al. (15). Previous studies had shown that deletion of the glial cells missing 2 (Gcm2) gene in the mouse resulted in failure of the development of the parathyroid glands (16). These animals exhibited only mild hypoparathyroidism. Both of these studies remind us that gene deletion may be a good way to “hunt for snarks”. The study by Tu et al. uncovered an auxiliary site for the regulation of calcium homeostasis: PTH production in the thymus. The importance of the role of this thymus source in humans is uncertain, since patients who have had all four parathyroids removed generally have severe hypoparathyroidism. The parathyroid hyperplasia that was observed by Kos et al. may be the signal for another snark hunt (Figure 1). The results imply that CaSR regulates parathyroid cell replication independently of PTH secretion. The development of primary hyperparathyroidism in transgenic mice over-expressing cyclin D1 (17) suggests the existence of such a pathway and it will be important to find out how CaSR might affect this pathway.
Figure 1Upon comparison with sex-matched control littermates (a) PTH–/–CaSR–/– mice exhibited parathyroid hyperplasia (b) (14). The enlargement of the parathyroid glands in PTH–/–CaSR–/– animals could indicate that CaSR plays an important regulatory role in limiting parathyroid size and cell replication.
The results of these two studies were concordant and perhaps disappointing in that both forms of rescue resulted in the production of mice with an essentially normal skeletal phenotype. However, there were abnormalities of calcium regulation. In the Gcm2-deficient mice hypocalciuria persisted while in the PTH-knockout animals there was increased expression of calcium transporters in the kidney and greater variability of serum calcium concentration and of urine calcium excretion. This is presumably due to absence of fine regulation by PTH.
Perhaps disappointing was the finding that the skeletal changes associated with CaSR deficiency were essentially abrogated in both models. The mice rescued by Gcm2 deficiency showed no detectable skeletal abnormalities while there was a small increase in bone mineral density of vertebrae of the female PTH–/– rescued animals but no significant changes by dynamic histomorphometry. However, neither model was subjected to perturbations of skeletal remodeling, which might bring out a role for CaSR. On the other hand, the results suggest that the severe osteomalacia seen in single knockout (Figure 2) is a direct consequence of PTH excess, and this raises new questions.
Figure 2Nondecalcified histologic sections of the tibia of 1-week-old (a) CasR-deficient, and (b) CasR- and Gcm2-deficient mice. Double knockout reverses the mineralization defect observed in CasR–/– mice. This result indicates that an excess of PTH may somehow directly produce a picture of rickets and osteomalacia and that this abnormality is not due to the absence of CaSR in bone cells. It will be important to find out what very high PTH levels might be doing to the proteins and transport systems that regulate mineralization in these mice.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)