Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas

Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Kobe University Graduate School of Medicine, Kobe, Japan. syano@rics.bwh.harvard.edu

OBJECTIVE: A significant decrease in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) protein expression has been demonstrated recently in parathyroid (PT) adenomas. In this study, we investigated the relationships between the proliferative activity of parathyroid glands (PTGs) and the expression of VDR as well as CaSR, and compared it with the clinical severity in patients with primary hyperparathyroidism (1 degrees HPT). DESIGN: Seven patients with 1 degrees HPT were included in this study. Four patients with thyroid carcinoma served as controls. METHODS: Immunohistochemical staining was performed on serial sections of PTGs with specific antibodies against CaSR, VDR, and Ki67. Areas examined in each section were selected at random in relation to the gland size. The number of Ki67-positive cells was expressed as a labeling index (LI; positive cells per 1000 PT cells). The expression of CaSR and VDR was semi-quantitatively analyzed based on the intensity of staining. After averages of the scores from all areas were calculated, CaSR and VDR scores, and Ki67 LI were assigned to each gland for use in statistical analyses. RESULTS: In PT adenomas, scores of VDR and CaSR were markedly lower than in normal PTGs (P<0.01), while the proportion of Ki67-positive cells in PT adenomas was significantly higher than in normal PTGs (P<0.01). Single regression analyses revealed that Ki67 LI was positively correlated with serum levels of intact parathyroid hormone and Ca, and PTG weight (R=0.70, P<0.05, R=0.78, P<0.01 and R=0.84, P<0.05 respectively). Ki67 LI was negatively correlated with CaSR and VDR scores (R=-0.78, P<0.01 and R=-0.72, P<0.05 respectively). Moreover, there was a strong positive relationship between CaSR and VDR expression (R=0.95, P<0.001). CONCLUSIONS: Marked decreases in VDR and CaSR expression could, at least in part, be responsible for the high proliferation of PT cells and the pathological progression of 1 degree HPT.

This article has been cited by other articles:

				P. Bjorklund, T. Krajisnik, G. Akerstrom, G. Westin, and T. E. Larsson Type I Membrane Klotho Expression Is Decreased and Inversely Correlated to Serum Calcium in Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4152 - 4157. [Abstract] [Full Text] [PDF]

				S. Yano, T. Yamaguchi, I. Kanazawa, N. Ogawa, K. Hayashi, M. Yamauchi, and T. Sugimoto The uraemic toxin phenylacetic acid inhibits osteoblastic proliferation and differentiation: an implication for the pathogenesis of low turnover bone in chronic renal failure Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3160 - 3165. [Abstract] [Full Text] [PDF]

				I. Titon, A. Cailleux-Bounacer, J. P. Basuyau, H. Lefebvre, A. Savoure, and J. M. Kuhn Evaluation of a standardized short-time calcium suppression test in healthy subjects: interest for the diagnosis of primary hyperparathyroidism Eur. J. Endocrinol., September 1, 2007; 157(3): 351 - 357. [Abstract] [Full Text] [PDF]

				T. Drueke, D. Martin, and M. Rodriguez Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies Nephrol. Dial. Transplant., July 1, 2007; 22(7): 1828 - 1839. [Full Text] [PDF]

				C. J. Haven, V. M. Howell, P. H. C. Eilers, R. Dunne, M. Takahashi, M. van Puijenbroek, K. Furge, J. Kievit, M.-H. Tan, G. J. Fleuren, et al. Gene Expression of Parathyroid Tumors: Molecular Subclassification and Identification of the Potential Malignant Phenotype Cancer Res., October 15, 2004; 64(20): 7405 - 7411. [Abstract] [Full Text] [PDF]

				R. A. Chen and W. G. Goodman Role of the calcium-sensing receptor in parathyroid gland physiology Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1005 - F1011. [Abstract] [Full Text] [PDF]