1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia

Szabó, András; Merke, J.; Beier, Eric; Mall, Gerhard; Ritz, Eberhard

doi:10.1038/ki.1989.89

Cited by 246 publications

(117 citation statements)

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“…Sufficient 1,25(OH) 2 D 3 suppresses not only PTH synthesis at the mRNA level but also PT cell proliferation through the VDR (13,14). Previous work also indicates the involvement of VDR down-regulation in the high proliferative activity of PTGs in 28HPT (16).…”

Section: Discussionmentioning

confidence: 84%

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

Yano

Sugimoto

Tsukamoto

et al. 2003

European Journal of Endocrinology

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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.

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Section: Discussionmentioning

confidence: 84%

“…VDR gene knockout mice have a similar phenotype (12). Vitamin D suppresses not only PTH synthesis at the mRNA level but also PT cell proliferation (13,14). In addition, VDR expression has been shown to be correlated negatively with PT growth potential in hemodialysis patients with 28HPT (7,15,16).…”

Section: Introductionmentioning

confidence: 96%

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

Yano

Sugimoto

Tsukamoto

et al. 2003

European Journal of Endocrinology

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“…Moreover, we found significant inhibition of cell proliferation resulting in lower cell numbers after treatment with vitamin D 3 , atRA or 9cRA. Previous studies have mostly indicated an inhibitory effect of vitamin D 3 on parathyroid cell proliferation (Slatopolsky et al 1984, Szabo et al 1989, although a lack of effect has also been reported (Naveh-Many et al 1995), whereas effects of retinoic acids have not been evaluated.…”

Section: +mentioning

confidence: 99%

Differentiation of human parathyroid cells in culture

Liu¹,

Ridefelt²,

Åkerström³

et al. 2001

Journal of Endocrinology

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Continuous culture of parathyroid cells has proven difficult, regardless from which species the cells are derived. In the present study, we have used a defined serum-free low calcium containing medium to culture human parathyroid cells obtained from patients with parathyroid adenomas due to primary hyperparathyroidism. No fibroblast overgrowth occurred, and the human parathyroid chief cells proliferated until confluent. After the first passage the cells ceased to proliferate, but still retained their functional capacity up to 60 days, demonstrated by Ca 2+ -sensitive changes in the release of parathyroid hormone (PTH) and as adequate cytoplasmic calcium ([Ca 2+ ] i ) responses to changes in ambient calcium as measured by microfluorimetry. Low calcium concentrations enhanced, and vitamin D 3 and retinoic acids (RA) dose-dependently inhibited cell proliferation during the first passage, as determined by [ 3 H]thymidine incorporation, immunohistochemistry for proliferating cell nuclear antigen and cell counting. Signs of differentiation were present as the set-points, defined as the external calcium concentration at which half-maximal stimulation of [Ca 2+ ] i (set-point c ), or half-maximal inhibition of PTH release (set-point p ) occur, were higher in not proliferating compared with proliferating cells in P0. Inhibition of cell proliferation was accompanied by signs of left-shifted set-points, indicating a link between proliferation and differentiation.The results demonstrate that human parathyroid chief cells cultured in a defined serum-free medium can be kept viable for a considerable time, and that signs of differentiation occur after proliferation has ceased. The low calcium stimulated cell proliferation may also be inhibited by vitamin D and RA.

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“…Not all studies have found similar results, however. In a study on rats by Szabo et al (28), 10 d of treatment with calcitriol from day 21 of uremia did not reverse existing hyperplasia. Furthermore, no apoptosis of the parathyroids could be induced in uremic rats, even by extremely high doses of calcitriol as reported by Naveh-Many et al (20) and Jara et al (29).…”

Section: Can Parathyroid Hyperplasia Be Arrested or Reversed?mentioning

confidence: 99%

Can Hyperparathyroid Bone Disease Be Arrested or Reversed?

Ølgaard

Lewin

2006

Clinical Journal of the American Society of Nephrology

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Parathyroid hyperplasia, oversecretion of parathyroid hormone (PTH), and hyperparathyroid bone disease are characteristic features of chronic uremia; they develop early in the course of uremia and often in a progressive way. This review focuses on the potential for arrest or regression of hyperparathyroid-induced bone disease. For this purpose, the review addresses investigations that have used bone histology and not investigations that indirectly attempted to demonstrate changes in the skeleton by measurements of bone mineral density or laboratory indices of bone turnover, other than PTH. A prerequisite for inducing regression of the hyperparathyroid bone disease is a significant suppression of PTH secretion or reversal of hyperparathyroidism and uremia. It is concluded, on the basis of paired bone biopsy studies in patients with established hyperparathyroid bone disease, that bone histology can be improved or normalized after treatment that diminishes PTH levels. Oversuppression of PTH levels, however, might lead to adynamic bone disease.Clin J Am Soc Nephrol 1: 367-373, 2006367-373, . doi: 10.2215 R enal osteodystrophy (ROD) is a disabling skeletal disease in uremic patients that consists of a high-turnover bone disease, a low-turnover bone disease, or a mixture of both. The type of bone lesion is correlated to increased production or to oversuppression of parathyroid hormone (PTH) levels (1-3).The high-turnover bone disease, osteitis fibrosa (cystica), is related to the severity of the secondary hyperparathyroidism (sHPT). PTH in concert with locally produced cytokines and factors (some produced by bone marrow cells and some by osteoblast precursors) IL-1 and TNF and later IL-6, IL-11, GM-CSF, M-CSF, and the OPG/RANKL system induce recruitment and differentiation of osteoclast precursors, resulting in stimulation of bone resorption (4). Bone formation is impaired, but the mechanism is not completely understood. PTH inhibits the synthesis of collagen and inhibits the progression of the osteoblastic cell cycle. The net result of severe sHPT in uremia is accelerated bone resorption. Furthermore, these bone lesions are characterized by massive peritrabecular fibrosis, and it has been postulated that PTH stimulates proliferation of an osteoprogenitor (preosteoblastic cell), which leads to accumulation of fibroblastic cells that produce marrow fibrosis (4). Recent experimental evidence (5,6) documented that uremia, per se, decreases skeletal anabolic activity. Development of HPT might be considered an adaptive mechanism to override this abnormality in bone remodeling. In this respect, increased PTH functions as a surrogate for a missing factor, maintaining bone turnover. Bone morphogenic protein 7 is a candidate for such a renal-derived factor (7,8).The clinical consequences of osteitis fibrosa, fractures, skeletal deformities, tendon rupture, bone pain, and impaired skeletal growth in children are well described. In the total population of uremic patients, hyperparathyroid bone lesions still are the most frequen...

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1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia

Cited by 246 publications

References 19 publications

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

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

Differentiation of human parathyroid cells in culture

Can Hyperparathyroid Bone Disease Be Arrested or Reversed?

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