Vitamin D-independent therapeutic effects of extracellular calcium in a mouse model of adult-onset secondary hyperparathyroidism.
Cell proliferation and PTH secretion in the parathyroid gland are known to be regulated by vitamin D and extracellular calcium. Here, we examined the vitamin D-independent effects of correction of extracellular calcium in an adult-onset secondary hyperparathyroidism (sHPT) model, using mice with a nonfunctioning vitamin D receptor (VDR). Wildtype and homozygous VDR mutant mice were kept on a rescue diet (RD) containing 2% calcium (Ca), 1.25% phosphorus (P), and 20% lactose until they were 4 mo or 1 yr of age. Subsequently, 4-mo-old mice were switched to a challenge diet (CD) containing the following: 0.5% Ca, 0.4% P, and 0% lactose. After 2 mo on the CD, groups of VDR mutant mice were either fed CD, a normal mouse chow with 0.9% Ca, 0.7% P, and 0% lactose, or the RD for another 3 mo. Feeding the RD protected VDR mutants against sHPT over 1 yr, showing that vitamin D is not essential for long-term control of the function and proliferation of parathyroid cells. When 4-mo-old VDR mutants were switched from the RD to the CD for 2 mo, they developed severe sHPT associated with hypertrophy and hyperplasia of parathyroid glands and profound bone loss. Subsequent feeding of the RD during a 3-mo therapy phase fully corrected sHPT, reduced chief cell proliferation, and reduced maximum parathyroid gland area by 25% by cell atrophy. There was no evidence of RD-induced chief cell apoptosis. We conclude that signaling by the calcium-sensing receptor regulates chief cell function and size in the absence of signaling through the VDR.
Weber
Karin
K
Institute of Animal Physiology, Ludwig Maximilians University, Munich, Germany.
Bergow
Claudia
C
Hirmer
Sieglinde
S
Schüler
Christiane
C
Erben
Reinhold G
RG