Transcriptional and Translational Regulation of Vitamin D Receptor (VDR) and Calcium Sensing Receptor (CaSR) in Patients With Sporadic Primary Hyperparathyroidism

Introduction:

Primary hyperparathyroidism (PHPT) is the third most frequent endocrine disorder, after diabetes mellitus and thyroid disorders, that predominantly affects postmenopausal women, with an incidence of 1 -5 in 1000 people. It can occur at any age though young people are rarely affected. PHPT is characterized by hypersecretion of parathyroid hormone (PTH) and resultant hypercalcemia. Most cases of PHPT (>85%) result from a solitary adenoma in one of the parathyroid glands. Multi-gland hyperplasia is found in about 10-15% of the patients while carcinoma occurs rarely (1-2%).

The parathyroid glands regulate calcium homeostasis. The major target organs for parathyroid hormone (PTH) are bone and the kidneys. PTH increases bone resorption to mobilize calcium into the circulation. In the kidney, PTH enhances calcium reabsorption and increases phosphate excretion. PTH also stimulates renal production of 1α,25-dihydroxyvitamin D [1,25(OH)2D], which in turn enhances intestinal absorption of calcium. Thus, the physiological effects of PTH are to increase the concentration of calcium in the circulation. Negative feedback from calcium and 1,25(OH)2D modulate parathyroid function. These effects are mediated via the calcium-sensing receptor (CaSR) expressed on the parathyroid cell surface. Similarly, 1,25(OH)2D, acts through vitamin D receptor (VDR) and suppresses PTH synthesis and secretion . Thus, PTH secretion is tightly coupled to the parathyroid cell's ambient calcium level.

Increased parathyroid cell proliferation and decreased calcium-mediated control of the PTH secretion are characteristic findings in all types of hyperparathyroidism (1-4). Calcium via its receptor, the CaSR and the 1,25(OH)2D-VDR complex are the most important regulators, in this respect. Decreased actions of these regulators would stimulate the parathyroid cells to proliferate. Molecular analyses have revealed the presence of tumor-specific DNA rearrangements in a subset of adenomas. In such rearrangements, the 5' PTH gene regulatory region combines upstream of the Cyclin D1 gene, which results in over expression of cyclins that could induce proliferation by increasing mitotic rate. In fact Cyclin D1 over expression was first demonstrated in a patient with parathyroid adenoma (5).

Impaired CaSR gene expression is found in parathyroid lesions of both primary and secondary hyperparathyroidism (6-11). No mutations could be found in CaSR gene in parathyroid neoplasias (11,12). Similar present findings shows reduced VDR gene expression (8,13-15) and concur with studies on the apparent lack of VDR gene mutations in hyperparathyroidism (16-18). Differential expression of VDR and CaSR gene has been reported in a few parathyroid adenomas, but exact mechanism is not known. These observations raise the possibility that altered expression of these genes could be related to the pathogenesis of parathyroid adenomas.