Genetic disorders – Development
Kidney International (2002) 62, 1196–1207; doi:10.1111/j.1523-1755.2002.kid585.x
Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism1
Masanori Tokumoto, Kazuhiko Tsuruya, Kyoichi Fukuda, Hidetoshi Kanai, Shoji Kuroki and Hideki Hirakata
Department of Medicine and Clinical Science, and Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence: Masanori Tokumoto, M.D., Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: tokumoto@intmed2.med.kyushu-u.ac.jp
1See Editorial by Dusso on p. 1472.
Received 16 July 2001; Revised 22 May 2002; Accepted 28 May 2002.
Abstract
Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism.
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.
Keywords:
uremia, hemodialysis, cyclin-dependent kinase inhibitor, PTH cell proliferation, parathyroidectomy, cell cycle
