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

Abstract

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 (18HPT). Design: Seven patients with 18HPT 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 ðP , 0:01Þ; while the proportion of Ki67-positive cells in PT adenomas was significantly higher than in normal PTGs ðP , 0:01Þ: Single regression analyses revealed that Ki67 LI was positively correlated with serum levels of intact parathyroid hormone and Ca, and PTG weight (R ¼ 0:70; P , 0:05; R ¼ 0:78; P , 0:01 and R ¼ 0:84; P , 0:05 respectively). Ki67 LI was negatively correlated with CaSR and VDR scores (R ¼ 20:78; P , 0:01 and R ¼ 20:72; P , 0:05 respectively). Moreover, there was a strong positive relationship between CaSR and VDR expression ðR ¼ 0:95; P , 0:001Þ: 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 18HPT.

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

“…Reduced CASR expression was also found in adenomas compared with normal parathyroid tissue cells, and the magnitude of reduction was similar to previous reports on patients probably having mild forms of PHPT (12,14,15,16,17,18). Decreased CASR expression in parathyroid adenomas would be consistent with a less efficient control of PTH synthesis and secretion by calcium.…”

“…Because the normal parathyroid tissues in our samples showed both nuclear and cytoplasmic positivity, we separately assessed nuclear and cytoplasmic VDR expression and found decreased expression of VDR at both cellular locations in parathyroid adenomas. This is the first time such a separate analysis has been performed as there is no mention of cytoplasmic VDR assessment in previous studies (13,14) presumably considered as non-specific staining (12). Nuclear localization of VDR with subsequent binding to vitamin D response elements (VDREs) in target genes is essential for vitamin D biological activity.…”

“…Abnormalities in VDR (12,13,14), CASR (14,15,16,17,18), and CD1 (19,20,21,22,23) expression have been reported in the cases probably having mild form of PHPT, parathyroid cancers, and renal secondary hyperparathyroidism. However, very little is known about such abnormalities in adenomas from patients with symptomatic sporadic PHPT (24,25,26).…”

Evaluation of a standardized short-time calcium suppression test in healthy subjects: interest for the diagnosis of primary hyperparathyroidism

“…This is possibly due to a lower sensitivity of adenomatous cells than hyperplastic parathyroid cells to calcium. Among the different mechanisms proposed to explain the relative insensitivity of parathyroid adenomas to calcium (10,15,16,51), the changes could be less profound in parathyroid cells from MEN1 patients than in sporadic PHP. However, a study of calcium-sensing receptor content or expression was not performed and this hypothesis cannot be confirmed in our cases.…”

“…However, adenomatous parathyroid cells appear less sensitive to the negative feedback of calcium than normal parathyroid cells (12)(13)(14). The molecular basis of this relative insensitivity was attributed to either a decrease in the number of calcium-sensing receptors, an alteration in the transduction system, or both (10,15,16). On this basis, a PTH suppression test using calcium loading has been proposed in order to differentiate PHP patients from subjects with normal parathyroid function (17).…”