Background: In uremic patients with secondary hyperparathyroidism (2HPT), nodular hyperplasia of parathyroid gland shows a monoclonal pattern of cell proliferation, in which a decreased density of vitamin D receptor (VDR) also is demonstrated. The present study aimed at elucidating the mechanism of parathyroid cell proliferation in relation to cell cycle determinants in patients with advanced 2HPT.
Methods: The expression of cyclin-dependent kinase inhibitors, p21 and p27, and VDR were examined and compared among four groups of nodular (Nd; N = 23) or diffuse (Df; N = 6) hyperplastic parathyroid glands resected due to 2HPT, primary adenomas (Ad; N = 15), and histologically-normal parathyroid glands (C; N = 20) removed during thyroidectomy. Immunohistochemical analyses for VDR, p21, p27 and Ki67 antigen were performed in formalin-fixed paraffin-embedded tissues by using specific polyclonal antibody. The distribution and the intensity of immunoreactivity was quantified by using NIH imaging, and was expressed as the labeling index (LI) of positive nuclear staining in a random set of 1000 cells.
Results: p21 LI was significantly diminished in both Nd (85 +/- 110; mean +/- SD) and Ad (136 +/- 122) as compared to that in Df (360 +/- 191) or C (359 +/- 228; P < 0.01). p27 LI was also significantly diminished in both Nd (97 +/- 156) and Ad (187 +/- 196) as compared to that in Df (532 +/- 146) or C (631 +/- 170; P < 0.01). VDR LI in Nd (162 +/- 194) was also significantly lower than that in Df (495 +/- 337), Ad (383 +/- 262), or C (659 +/- 234), respectively (P < 0.01). Parathyroid sections with high nuclear VDR expression elicited high p21 and p27 expression. Both p21 and p27 LI in Nd correlated significantly with nuclear VDR LI (r = 0.92; P < 0.01, r = 0.76; P < 0.01), but not with p53 LI, and inversely correlated with the glandular weight (r = 0.44; P < 0.05, r = 0.41; P < 0.05).
Conclusions: The reduced expression of p21 and p27, in a VDR-dependent manner, is a major pathogenic factor for a nodular parathyroid gland growth.