The role of calcium-sensing receptor abnormality in the pathogenesis of secondary hyperparathyroidism.

Abstract

because the nodular lesion is at an advanced stage of Introduction parathyroid hyperplasia. In order to elucidate the relationship of CaR and 2In uraemic secondary hyperparathyroidism (2-HPT), HPT more precisely, the expression of CaR mRNA a normal serum calcium (Ca) does not adequately and protein was studied in surgically resected parasuppress excessive parathyroid hormone (PTH) prothyroid glands of six patients with severe 2-HPT (intact duction and secretion [1]. This result suggests an PTH>800 pg/ml ) on haemodialysis. Light microscopy abnormal Ca-sensing mechanism in 2-HPT. The sensitshowed that all glands included hypertrophic and ivity of the parathyroid to extracellular Ca has been hyperplastic lesions with or without nodular change. evaluated by the sigmoidal curve between serum intact Immunohistological examination demonstrated the PTH and Ca concentrations [2]. Although there is decreased expression of CaR protein in all hyperplastic controversy that the set-point Ca concentration calcuparathyroid glands tissues, in particular in nodular lated from this curve precisely reflects the sensitivity hyperplastic lesions compared with diffuse lesions. In of the parathyroid cell for Ca [3–5], the depressed addition, the expression of CaR mRNA by quantitative sensitivity for Ca has been clearly shown in vitro and RT–PCR and Northern blotting analyses showed a by the common experience in severe 2-HPT that high PTH develops despite the unphysiological hypercalcaemore profound reduction in large nodular hyperplastic mia. The mechanism for this abnormality has been parathyroid glands compared to that in small hyperplpartially explained by decreased plasma-activated vitastic parathyroid glands. The finding that the expresamin D, an increased parathyroid cellular mass, or a sion of parathyroid gland CaR mRNA and protein reduced vitamin D receptor in the parathyroid gland. decreases particularly in large nodular hyperplastic However, the precise mechanism is not yet fully glands is consistent with the results of two previous understood. reports. We next evaluated the correlation between resected gland weight and the expression of CaR mRNA, which Ca-sensing receptor in 2-HPT was classified into four grades by mRNA density. A significant inverse correlation was observed between Since the discovery of the Ca-sensing receptor (CaR) the weight and CaR mRNA of resected parathyroid in bovine [6 ] and human parathyroid [7], much attenglands. tion has been directed at the relationship between CaR Parathyroid cells in nodular hyperplasia generally and abnormal sensitivity for Ca in 2-HPT. Kifor et al. show a greater proliferative change compared with first reported the decreased expression of CaR protein those in diffuse hyperplasia [11]. Therefore, the relation in parathyroid tissue [8]. This finding was also supbetween proliferative activity and CaR protein expresported by CaR mRNA levels [9]. sion in the parathyroid cell was examined. Proliferation These two reports together demonstrate that the was determined by proliferative cellular nuclear antigen downregulation of CaR is more remarkable in nodular (PCNA) staining. CaR protein was strongly expressed hyperplastic lesions of the parathyroid compared with in parathyroid tissue where the PCNA staining was that in diffuse lesions and that the same downregulation scarce. In contrast, CaR expression was rare in tissue is observed in the hyperplastic tissue of primary hyperwhere the PCNA was strongly stained. These results parathyroidism. Since hyperplastic parathyroid glands suggest that the proliferative potential of parathyroid display less sensitivity to Ca [10], it appears to be tissue inversely correlates with CaR expression and reasonable that CaR expression and the sensitivity for sensitivity for Ca. Ca are suppressed more in nodular hyperplastic glands, The relation between cell proliferation and expression of CaR is similar to that between cell proliferation Correspondence and offprint requests to: Tadao Akizawa, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227, Japan. and vitamin D receptor density [12]. Expression of