Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene

J Clin Invest. 2002 Dec;110(12):1849-57. doi: 10.1172/JCI14218.

Abstract

Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-alpha (CGRPalpha), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-) knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Comment

MeSH terms

  • Alternative Splicing
  • Animals
  • Bone Density*
  • Bone Resorption
  • Bone and Bones / anatomy & histology
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / physiology*
  • Calcitonin / genetics*
  • Calcitonin / physiology*
  • Calcitonin Gene-Related Peptide / genetics*
  • Calcitonin Gene-Related Peptide / physiology*
  • Estrogens / deficiency
  • Female
  • Gene Deletion
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoclasts / metabolism
  • Osteogenesis
  • Ovariectomy
  • Parathyroid Hormone / metabolism
  • Phenotype
  • Radiography
  • Thyroid Gland / cytology
  • Thyroid Gland / metabolism

Substances

  • Estrogens
  • Parathyroid Hormone
  • Calcitonin
  • Calcitonin Gene-Related Peptide