Influence of Vitamin D Deficiency on Cyclin D1-Induced Parathyroid Tumorigenesis

Abstract

Primary hyperparathyroidism (PHPT) is a common endocrinopathy for which several pathogenic mechanisms, including cyclin D1 overexpression, have been identified. Vitamin D nutritional status may influence parathyroid tumorigenesis, but evidence remains circumstantial. To assess the potential influence of vitamin D insufficiency/deficiency on initiation or progression of parathyroid tumorigenesis, we superimposed vitamin D insufficiency or deficiency on parathyroid tumor-prone parathyroid hormone-cyclin D1 transgenic mice. Mice were placed on diets containing either 2.75 IU/g, 0.25 IU/g, or 0.05 IU/g cholecalciferol, either prior to expected onset of PHPT or after onset of biochemical PHPT. When introduced early, superimposed vitamin D insufficiency/deficiency had no effect on serum calcium or on parathyroid gland growth. However, when introduced after the onset of biochemical PHPT, vitamin D deficiency led to larger parathyroid glands without differences in serum biochemical parameters. Our results suggest that low vitamin D status enhances proliferation of parathyroid cells whose growth is already being tumorigenically driven, in contrast to its apparent lack of direct proliferation-initiating action on normally growing parathyroid cells in this model. These results are consistent with the hypothesis that suboptimal vitamin D status may not increase incidence of de novo parathyroid tumorigenesis but may accelerate growth of a preexisting parathyroid tumor.

Keywords: PTH; primary hyperparathyroidism; vitamin D.

Figure 1.

Effect of dietary cholecalciferol content on serum vitamin D levels. Serum 25-hydroxyvitamin D (A, C) and 1,25-dihydroxyvitamin D (B, D) levels were measured from transgenic mice fed with the indicated diets. Administration of modified vitamin D diets was begun either at 3 months of age (top) or 10 months of age (bottom); n≥22 per dietary/genotype group; 2.75 = 2.75 IU/g diet, 0.25 = 025 IU/g diet, 0.05 = 0.05 IU/g diet.

Figure 2.

Effects of vitamin D status on initiation of PHPT. Three-month-old mice were fed with the indicated diets (2.75 = 2.75 IU/g diet, 0.25 = 025 IU/g diet, 0.05 = 0.05 IU/g diet) for 6 months. (A) Blood was collected at 2, 4, and 6 months on each diet and analyzed for total serum calcium (n≥9). Serum PTH (B, n≥21) and parathyroid gland volume (C) were measured after 6 months on each diet.

Figure 3.

Effects of vitamin D status on progression of preexisting PHPT. Ten-month-old mice were fed with the indicated diets (2.75 = 2.75 IU/g diet, 0.25 = 025 IU/g diet, 0.05 = 0.05 IU/g diet) for 6 months. (A) Blood was collected at 3 and 6 months on each diet and analyzed for total serum calcium (n≥9). (B) Serum PTH was measured at 6 months on each diet (n≥15). (C) Parathyroid gland volume (n≥4) was measured (*P < .002). (D) Proliferation, as measured by the number of Ki-67 + cells per 1000 cells (n≥4).