The calcium-sensing receptor and vitamin D receptor expression in tertiary hyperparathyroidism

Abstract

Abstract. The parathormone (PTH) production is controlled by calcium and vitamin D, which interact with the calciumsensing receptor (CaSR) and vitamin D receptor (VDR), respectively. All of these elements control calcium homeostasis, which is crucial for many physiological processes. Thus, impairment of the upstream component of this system, e.g. a decrease of CaSR and/or VDR, could result in hyperparathyroidism (HPTH). Therefore, the aim of this study was to assess the expression of CaSR and VDR in a tertiary form of HPTH (T-HPTH). The study involved 19 T-HPTH patients qualified for parathyroidectomy and 21 control parathyroids harvested from multi-organ cadaver donors. The small fragments of harvested glands were homogenized and used for Western blot analysis, whereas the remaining tissues underwent routine hematoxylin-eosin staining or immunostaining for CaSR and VDR. Among 64 T-HPTH parathyroids, 58 revealed the morphology of benign hyperplasia, 2 were identified as adenoma and 4 were classified as normal; some glands displayed a mixed histological phenotype. Western blot analysis revealed a decrease of CaSR and VDR in hyperplasia and adenomaderived samples. However, no correlation between the types of hyperplasia and receptor expression was observed. On the other hand, microscopic analysis of CaSR-and VDRimmunostained sections revealed a highly differentiated and significantly decreased mean expression of both receptors, which correlated with parathyroid histology. The reason behind the impaired expression of CaSR and VDR in T-HPTH is unclear. It presumably results from constant parathyroid stimulation at the stage of S-HPTH, followed by further development of polyclonal autonomy. However, the verification of this thesis requires further study. IntroductionThe production and secretion of parathormone (PTH), a main hormone produced by chief cells of parathyroid glands, remains under the control of calcium ions and vitamin D metabolites. The target molecules for these two key regulatory factors are calcium-sensing receptor (CaSR) and vitamin D receptor (VDR), respectively (1).Calcium-sensing receptor, which belongs to the class III of G-protein coupled receptors, could be activated by various di-and tri-valent cations, especially Ca 2+ and Mg 2+ , but also L-amino acids and other positively charged molecules (2). The triggering of CaSR by these agonists has been shown to post-transcriptionally down-regulate PTH expression, primarily by influencing the PTH-mRNA stability (1). The activation of CaSR also appears to inhibit parathyroid cell proliferation, however, the detailed molecular mechanism of this action remains unclear (3). Presumably, a useful model for the more precise determination of CaSR biological significance could be patients with loss-of-function receptor mutations, resulting in familial benign (hypocalciuric) hypercalcaemia (FBHH) or neonatal severe primary hyperparathyroidism (NSP-HPTH) (4).The receptor for vitamin D is the intracellular phosphoprotein belonging to the nuclear receptor superfa...

Bone health in chronic kidney disease‐mineral and bone disorder: a clinical case seminar and update

“…It acts on the sodium phosphate transporters in the renal tubules to promote phosphaturia and inhibits the action of 1‐alpha hydroxylase, further reducing 1, 25‐hydroxy‐vitamin D levels, with an additive effect of potentiating SHPT . Prolonged stimulation of the parathyroid glands may lead to tertiary hyperparathyroidism as a result of parathyroid tissue hyperplasia and downregulation of the calcium‐sensing and vitamin D receptors . This is a state of autonomously functioning parathyroid glands without appropriate responsiveness to plasma calcium concentrations.…”

Tertiary Hyperparathyroidism Pathogenesis, Clinical Features, and Medical Management

“…As a result of these molecular defects and because of continued stimulus from hyperphosphatemia, the size(s) of the parathyroid gland(s) is enormously increased-often several-fold and up to 25-fold over normal in some series. Reductions in VDR and CaSR expression, which appear to be necessary and sufficient for shifting the Ca-PTH set-point relationship, are more pronounced in the nodular compared to the internodular areas of these enlarged parathyroid glands [ 3,4,10 ] . This mechanism has been proposed to explain the lack of predictable responses to medical therapy with calcitriol and its analogues or with cinacalcet (see below).…”

“…Reduced expression of the calciumsensing (CaSR) and the vitamin D receptors (VDRs) has been demonstrated in these enlarged parathyroid glands both in experimental animal and human studies [ 10 ] . Other molecular abnormalities include overexpression of cell-cycle proteins, oncogenes involved in the multiple endocrine neoplasia type 1, and mutations in tumorsuppressor genes involved in tumorigenesis of sporadic primary parathyroid adenomas [ 2 ] .…”

“…Hyperphosphatemia leads to parathyroid cell proliferation and reduced expression of CaSR and VDR [ 1,[9][10][11] . In addition, hyperphosphatemia independently lowers the serum Ca, further exacerbating PTH hypersecretion [ 3,4 ] .…”

Vitamin D and calcium-sensing receptor polymorphisms differentially associate with resting energy expenditure in peripubertal children

“…Calcium is critical for cellular physiology, involved in a vast number of energy-dependent physiological processes (such as bone mineralization, muscle contraction, neuronal excitability and blood coagulation) which impact the storage and utilization of molecular, cellular and physiological resources [18;52]. …”