Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene.
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.
Hoff
Ana O
AO
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Catala-Lehnen
Philip
P
Thomas
Pamela M
PM
Priemel
Matthias
M
Rueger
Johannes M
JM
Nasonkin
Igor
I
Bradley
Allan
A
Hughes
Mark R
MR
Ordonez
Nelson
N
Cote
Gilbert J
GJ
Amling
Michael
M
Gagel
Robert F
RF
D017398:Alternative Splicing; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000502:physiology*; D002116:Calcitonin / Q000235:genetics* / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics* / Q000502:physiology*; D004967:Estrogens / Q000172:deficiency; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000378:metabolism; D010641:Phenotype; D011859:Radiography; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism
D004967:Estrogens; D010281:Parathyroid Hormone; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide