Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism.
The properties of neoplastic proliferation and hormonal dysregulation are tightly linked in primary hyperparathyroidism (HPT). However, whether abnormal parathyroid proliferation is the cause or result of a shift in calcium-sensitive parathyroid hormonal regulation has been controversial. We addressed this issue by analyzing the temporal sequence of these fundamental abnormalities in a mouse model of primary HPT. These transgenic mice (PTH-D1) harbor a transgene that targets overexpression of the cyclin D1 oncogene to parathyroid cells, resulting in parathyroid hypercellularity with a phenotype of chronic biochemical HPT and, notably, an abnormal in vivo PTH-calcium set point. We examined parathyroid cell proliferation and biochemical alterations in PTH-D1 and control wild-type mice from ages 1-14 months. Strikingly, abnormal parathyroid proliferation regularly preceded dysregulation of the calcium-PTH axis, supporting the concept that disturbed parathyroid proliferation is the crucial primary initiator leading to the development of the biochemical phenotype of HPT. Furthermore, we observed that decreased expression of the calcium-sensing receptor in the parathyroid glands occurs several months before development of biochemical HPT, suggesting that decreased calcium-sensing receptor may not be sufficient to cause PTH dysregulation in this animal model of primary HPT.
Mallya
Sanjay M
SM
Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Connecticut, USA.
Gallagher
James J
JJ
Wild
Yvette K
YK
Kifor
Olga
O
Costa-Guda
Jessica
J
Saucier
Kirsten
K
Brown
Edward M
EM
Arnold
Andrew
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015870:Gene Expression; D019940:Genes, bcl-1; D006961:Hyperparathyroidism / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000378:metabolism; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D013997:Time Factors
D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium