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

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

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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.

Original languageEnglish (US)
Pages (from-to)1029-1037
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number7
DOIs
StatePublished - Apr 1 2003

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Calcium-Sensing Receptors
Phenotype
Neuroglia
Skeleton
Parathyroid Glands
Hyperparathyroidism
Cartilage
Chondrogenesis
Physiologic Calcification
Osteomalacia
Rickets

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. / Tu, Qisheng; Pi, Min; Karsenty, Gerard; Simpson, Leigh; Liu, Shiguang; Quarles, L. Darryl.

In: Journal of Clinical Investigation, Vol. 111, No. 7, 01.04.2003, p. 1029-1037.

Research output: Contribution to journalArticle

Tu, Qisheng ; Pi, Min ; Karsenty, Gerard ; Simpson, Leigh ; Liu, Shiguang ; Quarles, L. Darryl. / Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 7. pp. 1029-1037.
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