Effects of Orai3-Mediated Store-Operated Calcium Entry on Parathyroid Hormone Release in Secondary Hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease, is characterized by elevated parathyroid hormone (PTH) secretion and Hypocalcemia. Orai3 is a highly selective calcium (Ca2+) channel that plays important roles in tumor development, cardiovascular disease, and autoimmune diseases; however, its role in SHPT is unclear. In the present study, RNA sequencing and western blot assays were used to detect the expression levels of Orai3 in parathyroid tissue from patients with SHPT and from individuals without SHPT. Ca2+ imaging was used to detect the effect of Orai3 channels on Ca2+ signaling in parathyroid gland cells. Enzyme-linked immunosorbent assays were used to detect changes in PTH release. Orai3 knockout rats were used to detect the effect of decreased Orai3 expression on serum PTH levels. We found that the expression of Orai3 in parathyroid tissue obtained from patients with SHPT was significantly higher than that in patients without SHPT. Knockdown of Orai3 in parathyroid cells by transfection with Orai3-specific small inhibitor RNA inhibited store-operated Ca2+ entry (SOCE) in parathyroid cells. Inhibition of SOCE or knockdown of Orai3 significantly inhibited PTH release in parathyroid cells. PTH levels in the blood of Orai3 knockout rat were significantly reduced. Therefore, Orai3 expression and Orai3-mediated Ca2+ signaling may be a mechanism underlying PTH release, and Orai3 may play a role in the development of SHPT.

Molecular genetic insights into sporadic primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

Disorders of plasma magnesium

Normal serum magnesium levels are in the range of 0.7–1.0 mmol/l and, as for calcium, most of the total body magnesium is found in bone and soft tissues. Magnesium is essential for normal cell metabolism (as a cofactor for numerous enzymes) and for neuronal function, and regulates parathyroid hormone release. Alterations in serum magnesium levels are usually asymptomatic unless severe. As there are large tissue reserves of magnesium, hypomagnesaemia usually only develops with chronic gastrointestinal or renal losses, or prolonged dietary insufficiency. Hypermagnesaemia is almost always iatrogenic, due to excessive supplementation. This chapter reviews the causes and management of derangements of plasma magnesium.