TY - JOUR
T1 - Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene
AU - Hoff, Ana O.
AU - Catala-Lehnen, Philip
AU - Thomas, Pamela M.
AU - Priemel, Matthias
AU - Rueger, Johannes M.
AU - Nasonkin, Igor
AU - Bradley, Allan
AU - Hughes, Mark R.
AU - Ordonez, Nelson
AU - Cote, Gilbert J.
AU - Amling, Michael
AU - Gagel, Robert F.
PY - 2002/12
Y1 - 2002/12
N2 - Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-α (CGRPα), 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 CGRPα 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.
AB - Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-α (CGRPα), 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 CGRPα 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.
UR - http://www.scopus.com/inward/record.url?scp=0036945790&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036945790&partnerID=8YFLogxK
U2 - 10.1172/JCI200214218
DO - 10.1172/JCI200214218
M3 - Article
C2 - 12488435
AN - SCOPUS:0036945790
SN - 0021-9738
VL - 110
SP - 1849
EP - 1857
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -