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

Presentation Number: OR05-1
Date of Presentation: April 3rd, 2017

Jessica Costa-Guda*1, Kristin Corrado2, Justin Bellizzi2, Elizabeth Saria2, Kirsten Saucier2, Miriam Guemes-Aragon3, Guntas Kakar3, John Vu2, Madison Rose2, Cynthia Alander2, Sanjay M Mallya3 and Andrew Arnold4
1University of Connecticut School of Dental Medicine, Farmington, CT, 2University of Connecticut School of Medicine, 3UCLA School of Dentistry, Los Angeles, CA, 4Univ of Connecticut Sch of Med, Farmington, CT


Primary hyperparathyroidism (PHPT) is a common clinical endocrinopathy for which a number of pathogenic mechanisms have already been identified. Among the most common is the overexpression of cyclin D1 seen in 20-40% of sporadic parathyroid adenomas, which led to the development of a mouse model of PHPT through parathyroid-targeted overexpression of cyclin D1. To assess the potential influence of vitamin D insufficiency/deficiency on the initiation or progression of parathyroid tumorigenesis, we utilized this parathyroid tumor-prone PTH-cyclin D1 transgenic mouse model and superimposed vitamin D insufficiency or deficiency either early (prior to the expected onset of PHPT) or late (after the onset of biochemical PHPT) in the course of PHPT. Importantly, because the dietary calcium can be maintained at a high level, this model system allows for the investigation of effects of vitamin D status independent of calcium. PTH-Cyclin D1 transgenic and wild type littermates were placed on one of three custom diets containing predefined levels of cholecalciferol: Standard (2.75 IU/g cholecaliferol), 0.25 IU/g (25% of murine recommended daily intake, RDI), or 0.05 IU/g (5% of murine RDI) cholecalciferol. All diets were replete for calcium. Mice were initiated on the diets at either 3 (early) or 10 (late) months of age and maintained on the diets ad libitum for 3-6 months prior to euthanasia. Mice on the standard diet maintained normal serum 25-hydroxyvitamin D levels, whereas the 0.25 IU/g and the 0.05 IU/g diets induced vitamin D insufficiency, and moderate to severe vitamin D deficiency, respectively. When introduced early, the 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 in our mouse model led to larger parathyroid gland sizes without differences in serum biochemical parameters. Our results suggest that low vitamin D status enhances the progressive 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 (or 'pre-tumorigenic') parathyroid cells in this model. In terms of clinical implications, these results are consistent with the hypothesis that suboptimal vitamin D status may not generally increase the incidence of de novo primary parathyroid tumorigenesis/neoplasia, or clinically-apparent disease, but may well help accelerate the growth of a pre-existing parathyroid tumor.


Nothing to Disclose: JC, KC, JB, ES, KS, MG, GK, JV, MR, CA, SMM, AA