Cellular physiology and pathophysiology of the parathyroid glands

Abstract

This report provides insight into parathyroid gland physiology and the pathophysiology of hyperparathyroidism (HPT). Increases in the extracellular calcium concentration constitute the primary physiological signal for inhibition of parathyroid hormone (PTH) release. Transduction of the external signal into a cellular response involves activation of a cation receptor mechanism on the plasma membrane with rapid rise in the cytoplasmic calcium concentration of the cells. This recently discovered parathyroid calcium receptor has been characterized as a glycoprotein of unusually high molecular weight, which may play a key role in calcium homeostasis since it is also expressed in the kidney and placenta. Binding of external calcium to the receptor is associated with mobilization of intracellular calcium as well as calcium influx into the cells and phosphoinositol hydrolysis. These events rapidly interfere with the release process through essentially unknown mechanisms and probably also at sustained stimulation inhibit PTH gene transcription. The relative calcium insensitivity of the PTH release in HPT is associated with a deranged regulation of cytoplasmic calcium within pathological parathyroid cells. The molecular basis for this disturbance comprises down regulation of the cation receptor, whereby external calcium is translated into abnormally low levels of cytoplasmic calcium and insufficient inhibition of PTH release. Studies on expression of the functionally important cation sensing glycoprotein and its associated cellular signal systems may provide novel means for interference with the pathophysiological derangements of HPT.

Subtotal parathyroidectomy for secondary renal hyperparathyroidism: a 20-year surgical outcome study

“…High phosphate levels, low or normal calcium concentration values, and vitamin D deficit play the fundamental role in the pathogenesis of the disease. Disturbances of the mutual correlations of the above factors result in uncontrolled, diffuse proliferation of parathyroid cells (polyclonal proliferation) in the initial stages of the disease, and subsequently in nodular proliferation (monoclonal proliferation) in patients with higher stages of chronic kidney disease [1–5]. The introduction of chronic dialysis programs, administration of vitamin D-derived, and phosphate-binding pharmaceuticals, as well as medications that regulate the activity of the calcium receptors through their continuous activation (calcimimetic agents) have markedly improved the situation of this group of patients.…”

Inverse relation between mRNA synthesis and secretion of parathyroid hormone in athymic mice grafted with human parathyroid tissueNote

“…In normal PT tissue, hypercalcemia leads to a decrease in PTH secretion by its action on the PT cell calcium receptor (10). It has also been shown in cell culture from normal PT tissue that chronic high calcium levels lead to a fall in PTH mRNA synthesis (11,12).…”

“…In adenomatous PT tissue this regulation by extracellular calcium is disturbed, i.e. at elevated extracellular calcium concentration, PTH secretion is not inhibited despite reduced PTH mRNA synthesis (10). This probably explains why, despite a gradual reduction of PTH mRNA expression, serum concentration of PTH can increase.…”

Effects of Pamidronate and Calcitriol on the Set Point of the Parathyroid Gland in Postmenopausal Hemodialysis Patients with Secondary Hyperparathyroidism

“…However, with the progression of parathyroid gland hyperplasia, the set point tends to increase even though extracellular calcium is still markedly reduced [23]. Thus, parathyroid cells from uremic patients require higher extracellular calcium concentrations than normal cells in order to suppress secretion of PTH [24]. After pamidronate treatment, the significant decrease in plasma iCa base levels associated with increased plasma PTH base levels might be due to pamidronate-induced hypocalcemic aggravation of SHP.…”