Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells

Mizobuchi, Masahide; Ogata, Hiroaki; Hatamura, Ikuji; Saji, Fumie; Koiwa, Fumihiko; Kinugasa, Eriko; Koshikawa, Shozo; Akizawa, Tadao

doi:10.1016/j.bbrc.2007.07.177

Cited by 56 publications

(49 citation statements)

References 22 publications

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“…We have to keep in mind three background points: (a) We and others have shown that oxyphil cells are well represented in NH (9,11). Recently, it was shown that oxyphil cells produce actively PTH-related protein and that oxyphil cells have a level of proliferation lower than that of chief cells (14); PTH-related protein could act through an autocrine/paracrine mechanism to regulate proliferation and differentiation of parathyroid cells (14), favoring their metaplastic change into the oxyphil phenotype (14,15); (b) CaR are expressed in many tissues, with the highest density being found in the chief cells of the parathyroid glands (2); (c) furthermore, very recently, it was also shown that CaR activation by the calcimimetic R-568 accelerates chief cell death, probably through an apoptotic mechanism in uremic rats in vitro (16). Thus, the hypothesis could be made that cinacalcet counteracts SHPT mainly through two synergistically operating mechanisms: An antiproliferative and a proapoptotic action on chief cells.…”

Section: Discussionmentioning

confidence: 99%

Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Lomonte¹,

Vernaglione²,

Chimienti³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: Vitamin D receptor activation by vitamin D sterols and calcium-sensing receptor stimulation by cinacalcet are the most powerful treatments of secondary hyperparathyroidism. This study was aimed to assess a possible association between histopathologic changes of parathyroid tissue and treatment modality.Design, setting, participants, & measurements: Studies were performed on 82 parathyroids of 22 adult white hemodialysis patients undergoing first parathyroidectomy. The type of hyperplasia and the distribution of chief and oxyphil cells, expressed as oxyphil/chief cell ratio, were assessed. Three groups could be studied according to treatment modality: group A consisted of 6 patients who were treated with cinacalcet, intravenous calcitriol, and phosphate binders; group B consisted of 6 patients who were treated with intravenous calcitriol and phosphate binders, and group C consisted of 10 patients who were treated with phosphate binders alone.Results: Sixty-eight (82.9%) out of 82 glands removed showed nodular hyperplasia. It was more frequent in groups A and B than in group C. A stepwise forward logistic regression model showed that the probability of nodular hyperplasia was higher in patients who were on calcitriol and/or cinacalcet therapy, in female gender and in patients with a higher body mass index. Oxyphil/chief cell ratio also was significantly different among the three groups. Cinacalcet treatment was the only predictor of this ratio.Conclusions: An association was found between calcitriol and/or cinacalcet therapy and a high prevalence of nodular hyperplasia, and between cinacalcet therapy and high oxyphil/chief cell ratio. The meaning of the observed associations remains uncertain.

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Section: Discussionmentioning

confidence: 99%

Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Lomonte¹,

Vernaglione²,

Chimienti³

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…Thus, the use of calcimimetics led to a decrease in PTH synthesis and PTH release (17); modulated the regulation of genes involved in these processes, including upregulation of CaR (18) and VDR (19); reduced parathyroid cell proliferation (20); attenuated progression of parathyroid hyperplasia (21,22); and enhanced parathyroid cell apoptosis (23). In experimental animals, calcimimetics attenuated or even halted the progression of osteitis fibrosa (24).…”

Section: Development Of Calcimimetics and Calcilyticsmentioning

confidence: 99%

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Drüeke¹,

Ritz²

2009

Clinical Journal of the American Society of Nephrology

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The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics.

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“…Cinacalcet increases the sensitivity of CaSR to activation by extracellular Ca and suppresses the release of iPTH. The CaSR play a key role in the excessive cell proliferation in PTG hyperplasia (17,18,19,20,21,22,23). In humans, the regression of PTG hyperplasia has been reported rarely, in cases of spontaneous infarction of the glands (24,25) and in cases of DH after kidney transplantation (26,27).…”

Section: Introductionmentioning

confidence: 99%

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy

Vulpio

Bossola

Stasio

et al. 2013

European Journal of Endocrinology

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Background: Cinacalcet is a new effective treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients (HP), but the alterations of parathyroid gland (PTG) hyperplasia determined by cinacalcet and vitamin D have not been extensively investigated in humans. Methods: We performed histological analyses of 94 PTGs removed from 25 HP who underwent parathyroidectomy (PTx) because of SHPT refractory to therapy with vitamin D alone (group AZ13 HP and 46 PTGs) or associated with cinacalcet (group BZ12 HP and 48 PTGs). The number, weight, the macroscopic cystic/hemorrhagic changes, and type of hyperplasia of PTG (nodularZNH, diffuseZDH) were assessed. In randomly selected HP of group A (4 HP and 14 PTGs) and group B (4 HP and 15 PTGs), the labeling index of cells positive to Ki-67 and TUNEL and the semiquantitative score of immunohistochemistry staining of vitamin D receptor, calcium-sensing receptor, and vascular endothelial growth factor-a (VEGF-a) were measured in the entire PTGs and in the areas with DH or NH. Results: The number and weight of single and total PTG of each HP were similar in the two groups as well as the number of PTG with macroscopic cystic/hemorrhagic areas. TUNEL, Ki-67, and VEGF-a scores were higher in NH than in DH areas. Conclusion: This observational study of a highly selected population of HP, submitted to PTx because SHPT refractory to therapy, shows that the macroscopic, microscopic, and immunochemistry characteristics of PTG in HP who received or did not receive cinacalcet before PTx did not differ significantly.

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Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells

Cited by 56 publications

References 22 publications

Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy

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