Parathyroid Cell Growth in Patients with Advanced Secondary Hyperparathyroidism: Vitamin D Receptor, Calcium Sensing Receptor, and Cell Cycle Regulating Factors

Abstract

The parathyroid gland (PTG) is a unique endocrine organ in which the quiescent glandular cells begin to proliferate in response to the demand for maintaining calcium (Ca) homeostasis in the progressive course of renal failure, leading to secondary hypereparathyroidism (SHPT). SHPT is characterized with continuous over-secretion of parathyroid hormone (PTH) and high turn-over bone disease, osteitis fibrosa, and the major factors include a deficiency of active vitamin D, hypocalcemia, and phosphate retention. With long-term end-stage renal failure, SHPT becomes resistant to conventional medical treatment such as phosphate binders and active vitamin D supplementation, and the growth of the PTG accelerates with the pattern of hyperplasia changing from diffuse to nodular type. In this process, the sigmoid curve between extracellular Ca concentration (exCa) and the plasma level of PTH shifts to the upper-rightward, indicating both an absolute increase in PTH secretion and the resistance of PT cells to exCa. Many experimental and human studies have revealed down-regulation of vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and retinoid X receptor (RXR) in PT cells. The sustained proliferation of PT cells after obtaining autonomicity is another characteristic feature of SHPT. In this context, it has been demonstrated that the cell cycle is markedly progressed, where the expression of cyclin-dependent kinase inhibitor (CDKI), p21 and p27, is depressed in a VDR-dependent manner. These pathological features are most evident in nodular hyperplasia, in which monoclonal proliferation is obvious, indicating the phenotypic changes have occured in PT cells. It has been observed by Fukagawa and colleagues that pharmacologically high dose of active vitamin D administered orally can cause small-size PTG hyperplasia to regress in patients with advanced SHPT. Successful renal transplantation may also restore VDR and CaSR expressions in the diffuse type, in association with increasing TUNEL-positive cells. Thus, it is important to vigorously treat SHPT when the PT cell proliferation is in the reversible stage of diffuse hyperplasia.

Calcium-sensing receptor in cancer: good cop or bad cop?

“…No correlation was seen between CaR mRNA in the adenoma and preoperative serum calcium, PTH, or weight of the adenoma [23]. Alterations in CaR expression may contribute to disturbances in cell cycle regulation and to monoclonal cell growth in parathyroid tissue [24].…”

GPRC6A Mediates the Non-genomic Effects of Steroids

“…S4), and cotransfection of GPRC6A and AR reduces AR-mediated gene transcription in response to testosterone. There are precedents in other biological systems for coordination between a GPCR and steroid receptor, such as CaSR and VDR regulation of parathyroid gland function (65). Typically the GPCR regulates acute changes and the steroid receptor leads to more long-term regulation of gene expression.…”

Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?

“…17 Since expression of messenger RNA for Klotho in the kidneys is reduced in patients with CKD, end-organ resistance to FGF23 could also contribute to the increased circulating FGF23 levels in advancing renal failure, 18 in a manner analogous to the role of end-organ resistance to PTH in hyperparathyroidism. 19 Regardless, dietary phosphate restriction increases renal production of 1,25(OH) 2 D in CKD, 20 possibly via reductions in FGF23 production.…”