Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background
Qisheng Tu, … , Shiguang Liu, L. Darryl Quarles
Qisheng Tu, … , Shiguang Liu, L. Darryl Quarles
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):1029-1037. https://doi.org/10.1172/JCI17054.
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Article Bone biology

Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background

Abstract

To understand the role of the calcium-sensing receptor (CasR) in the skeleton, we used a genetic approach to ablate parathyroid glands and remove the confounding effects of elevated parathyroid hormone (PTH) in CasR-deficient mice. CasR deficiency was transferred onto the glial cells missing 2–deficient (Gcm2-deficient) background by intercrossing CasR- and Gcm2-deficient mice. Superimposed Gcm2 deficiency rescued the perinatal lethality in CasR-deficient mice in association with ablation of the parathyroid glands and correction of the severe hyperparathyroidism. In addition, the double homozygous CasR- and Gcm2-deficient mice demonstrated healing of the abnormal mineralization of cartilage and bone associated with CasR deficiency, indicating that rickets and osteomalacia in CasR-deficient mice are not due to an independent function of CasR in bone and cartilage but to the effect of severe hyperparathyroidism in the neonate. Analysis of the skeleton of 6-week-old homozygous CasR- and Gcm2-deficient mice also failed to identify any essential, nonredundant role for CasR in regulating chondrogenesis or osteogenesis, but further studies are needed to establish the function of CasR in the skeleton. In contrast, concomitant Gcm2 and CasR deficiency failed to rescue the hypocalciuria in CasR-deficient mice, consistent with direct regulation of urinary calcium excretion by CasR in the kidney. Double Gcm2- and CasR-deficient mice provide an important model for evaluating the extraparathyroid functions of CasR.

Authors

Qisheng Tu, Min Pi, Gerard Karsenty, Leigh Simpson, Shiguang Liu, L. Darryl Quarles

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Figure 1

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Survival of CasR- and Gcm2-deficient mice. The survival rate of group I,...
Survival of CasR- and Gcm2-deficient mice. The survival rate of group I, which combines data from heterozygous Gcm2+/– and wild-type mice (n = 38), was 100%, whereas no group II homozygous CasR-deficient mice (n = 29) survived beyond 3 weeks. Group III homozygous Gcm2-deficient mice (n = 13) had a survival rate of 69%. The survival rates of group IV double homozygous CasR- and Gcm2-deficient mice (71%, n = 14) and group VI mixed heterozygous CasR- and homozygous Gcm2-deficient mice (74%, n = 23) are not different from that of group III Gcm2–/– mice. Group V, which combines heterozygous CasR+/– mice and the double heterozygous Gcm2+/–/CasR+/– mice (n = 69), had a survival rate of 97%.