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Human Molecular Genetics Advance Access originally published online on April 20, 2005
Human Molecular Genetics 2005 14(11):1515-1528; doi:10.1093/hmg/ddi160
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development

Yingben Xue1, Andrew C. Karaplis2, Geoffrey N. Hendy1, David Goltzman1 and Dengshun Miao1,*

1Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada and 2Lady Davis Research Institute, Sir Mortimer B. Davis—Jewish General Hospital and Department of Medicine McGill University, Montreal, Quebec H3T 1E2, Canada

* To whom correspondence should be addressed at: Calcium Research Laboratory, Rm: H4.67, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. Tel: +1 5148431632; Fax: +1 5148431712; Email: dengshun.miao{at}mcgill.ca

Received February 19, 2005; Accepted April 11, 2005

In humans, loss-of-function mutations in parathyroid hormone (PTH) and 25-hydroxyvitamin D3-1{alpha}-hydroxylase [1{alpha}(OH)ase] genes lead to isolated hypoparathyroidism and vitamin D-dependent rickets type I, respectively. To better understand the relative contributions of PTH and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to skeletal and calcium homeostasis, we compared mice with targeted disruption of the PTH or 1{alpha}(OH)ase genes to the double null mutants. Although PTH–/– and 1{alpha}(OH)ase–/– mice displayed only moderate hypocalcemia, PTH–/–1{alpha}(OH)ase–/– mice died of tetany with severe hypocalcemia by 3 weeks of age. At 2 weeks, PTH–/– mice exhibited only minimal dysmorphic changes, whereas 1{alpha}(OH)ase–/– mice displayed epiphyseal dysgenesis which was most severe in the double mutants. Although reduced osteoblastic bone formation was seen in both mutants, PTH deficiency caused only a slight reduction in long bone length but a marked reduction in trabecular bone volume, whereas 1{alpha}(OH)ase ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length. The results therefore show that PTH plays a predominant role in appositional bone growth, whereas 1,25(OH)2D3 acts predominantly on endochondral bone formation. Although PTH and 1,25(OH)2D3 independently, but not additively, regulate osteoclastic bone resorption, they do affect the renal calcium transport pathway cooperatively. Consequently, PTH and 1,25(OH)2D3 exhibit discrete and collaborative roles in modulating skeletal and calcium homeostasis and loss of the renal component of calcium conservation might be the major factor contributing to the lethal hypocalcemia in double mutants.


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