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

Abstract

In humans, loss-of-function mutations in parathyroid hormone (PTH) and 25-hydroxyvitamin D3-1alpha-hydroxylase [1alpha(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 1alpha(OH)ase genes to the double null mutants. Although PTH-/- and 1alpha(OH)ase-/- mice displayed only moderate hypocalcemia, PTH-/-1alpha(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 1alpha(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 1alpha(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.

• Authors: Yingben Xue, Andrew C Karaplis, Geoffrey N Hendy, David Goltzman, Dengshun Miao
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 14 Issue 11 Pg. 1515-28 (Jun 01 2005) ISSN: 0964-6906 [Print] England
• PMID: 15843402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Parathyroid Hormone
• Calcitriol
• Calcium

Topics

• Animals
• Base Sequence
• Blotting, Western
• Bone Development (physiology)
• Bone Resorption
• Calcitriol (physiology)
• Calcium (metabolism)
• DNA Primers
• Growth Plate (cytology)
• Homeostasis (physiology)
• Ion Transport
• Kidney (metabolism)
• Mice
• Mice, Knockout
• Models, Genetic
• Osteoclasts (cytology)
• Parathyroid Hormone (physiology)
• Polymerase Chain Reaction