Methylation Status of the CpG Islands in Vitamin D and Calcium-Sensing Receptor Gene Promoters Does Not Explain the Reduced Gene Expressions in Parathyroid Adenomas

Varshney, Shweta; Bhadada, Sanjay Kumar; Sachdeva, Naresh; Arya, Ashutosh Kumar; Saikia, Uma Nahar; Behera, Arunanshu; Rao, Sudhaker D

doi:10.1210/jc.2013-1699

Cited by 37 publications

(37 citation statements)

References 24 publications

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“…In HPT, various alterations inactivating CaSR signalling pathway can occur, causing excess PTH secretion 7 11 13 33 42 78 81 141 166. Furthermore, if downregulation of CaSR persists over time, studies have shown that it can lead to aberrant cell growth and proliferation (thought to be related to aberrant Wnt/β-catenin and cyclin D1 signalling), suggesting that CaSR signalling may serve a tumour suppressor function in the parathyroid glands 7 11 33 42 78 81 141 152 166 170–172…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

“…Despite its well-documented role in hereditary HPT, somatic mutations of the CaSR gene have not been identified in sporadic disease 13 42 76 141 152 200. Nonetheless, several studies reported that a significant subset of sporadic parathyroid adenomas display aberrant CaSR signalling , characterised by reduced expression of VDRs and CaSRs 13 42 76 141 150 152 172 200–204.…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

“…Nonetheless, several studies reported that a significant subset of sporadic parathyroid adenomas display aberrant CaSR signalling , characterised by reduced expression of VDRs and CaSRs 13 42 76 141 150 152 172 200–204. The exact mechanism underlying loss of expression of VDR and CaSR remains unclear, although genetic and epigenetic alterations in their respective genes have been sought but not found 13 42 76 141 150–152 172 200–204.…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

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Clinicopathological correlates of hyperparathyroidism

2015

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Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

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Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

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Clinicopathological correlates of hyperparathyroidism

2015

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“…No abnormal methylation of the CaSR gene has been found in parathyroid adenomas 118 but other epigenetic changes 90 have not been studied. Similar comments apply to vitamin D receptor expression, which was substantially reduced in more than 90% of cells for both translation 113,118 and transcription 116 with no abnormal methylation. 118 Since calcitriol increases CaSR expression, 119 loss of VDR could also account for reduced CaSR in parathyroid tumors and could be the initial epigenetic abnormality.…”

Section: Clinical Aspects Of Primary Hyperparathyroidismmentioning

confidence: 68%

“…Similar comments apply to vitamin D receptor expression, which was substantially reduced in more than 90% of cells for both translation 113,118 and transcription 116 with no abnormal methylation. 118 Since calcitriol increases CaSR expression, 119 loss of VDR could also account for reduced CaSR in parathyroid tumors and could be the initial epigenetic abnormality. A strong argument against the set point hypothesis is that parathyroid cell overexpression of cyclin D1 in transgenic mice leads to an early increase in proliferation and later to increased secretory set point, 120,121 but the force of this argument is reduced by the observation that the cyclin D1-induced proliferation in this model can be completely prevented by a calcimimetic drug that mimics an increase in CaSR set point.…”

Section: Clinical Aspects Of Primary Hyperparathyroidismmentioning

confidence: 68%

Parathyroid Growth

2015

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PTH and Vitamin D

Khundmiri

Murray

Lederer

2016

Comprehensive Physiology

216

158

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PTH and Vitamin D are two major regulators of mineral metabolism. They play critical roles in the maintenance of calcium and phosphate homeostasis as well as the development and maintenance of bone health. PTH and Vitamin D form a tightly controlled feedback cycle, PTH being a major stimulator of vitamin D synthesis in the kidney while vitamin D exerts negative feedback on PTH secretion. The major function of PTH and major physiologic regulator is circulating ionized calcium. The effects of PTH on gut, kidney, and bone serve to maintain serum calcium within a tight range. PTH has a reciprocal effect on phosphate metabolism. In contrast, vitamin D has a stimulatory effect on both calcium and phosphate homeostasis, playing a key role in providing adequate mineral for normal bone formation. Both hormones act in concert with the more recently discovered FGF23 and klotho, hormones involved predominantly in phosphate metabolism, which also participate in this closely knit feedback circuit. Of great interest are recent studies demonstrating effects of both PTH and vitamin D on the cardiovascular system. Hyperparathyroidism and vitamin D deficiency have been implicated in a variety of cardiovascular disorders including hypertension, atherosclerosis, vascular calcification, and kidney failure. Both hormones have direct effects on the endothelium, heart, and other vascular structures. How these effects of PTH and vitamin D interface with the regulation of bone formation are the subject of intense investigation.

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Methylation Status of the CpG Islands in Vitamin D and Calcium-Sensing Receptor Gene Promoters Does Not Explain the Reduced Gene Expressions in Parathyroid Adenomas

Abstract: Methylation-mediated silencing of VDR and CASR promoter does not appear to be associated with reduced expression, indicating the involvement of other factors in specific suppression of VDR and CASR in parathyroid adenomas.

Cited by 37 publications

References 24 publications

Clinicopathological correlates of hyperparathyroidism

Clinicopathological correlates of hyperparathyroidism

Parathyroid Growth

PTH and Vitamin D

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