Hypomorphic expression of parathyroid Bmal1 disrupts the internal parathyroid circadian clock and increases parathyroid cell proliferation in response to uremia.

The molecular circadian clock is an evolutionary adaptation to anticipate recurring changes in the environment and to coordinate variations in activity, metabolism and hormone secretion. Parathyroid hyperplasia in uremia is a significant clinical challenge. Here, we examined changes in the transcriptome of the murine parathyroid gland over 24 hours and found a rhythmic expression of parathyroid signature genes, such as Casr, Vdr, Fgfr1 and Gcm2.

A molecular circadian clock operates in the parathyroid gland and is disturbed in chronic kidney disease associated bone and mineral disorder.

Circadian rhythms in metabolism, hormone secretion, cell cycle and locomotor activity are regulated by a molecular circadian clock with the master clock in the suprachiasmatic nucleus of the central nervous system. However, an internal clock is also expressed in several peripheral tissues. Although about 10% of all genes are regulated by clock machinery an internal molecular circadian clock in the parathyroid glands has not previously been investigated.

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease.

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass.

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease.

The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice.

Micro-RNAs in the parathyroid: a new portal in understanding secondary hyperparathyroidism.

Purpose Of Review: Micro-RNAs (miRNAs) are important to the function of many cells including endocrine systems. We present the reported changes in miRNA profiles in parathyroid adenomas and carcinomas. We review the essential roles of parathyroid miRNAs to the response of the parathyroid to hypocalcemia and uremia.

The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia.

Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats.

Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia.

MicroRNAs (miRNAs) down-regulate gene expression and have vital roles in biology but their functions in the parathyroid are unexplored. To study this, we generated parathyroid-specific Dicer1 knockout (PT-Dicer(-/-) ) mice where parathyroid miRNA maturation is blocked. Remarkably, the PT-Dicer(-/-) mice did not increase serum parathyroid hormone (PTH) in response to acute hypocalcemia compared with the >5-fold increase in controls.

FGF-23 and secondary hyperparathyroidism in chronic kidney disease.

The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3.

FGF23 and the parathyroid glands.

Fibroblast growth factor 23 (FGF23) is a phosphatonin that is secreted by osteocytes and osteoblasts in response to hyperphosphatemia and 1,25-dihydroxyvitamin D (1,25D). It acts on its receptor complex, Klotho-FGFR1c (fibroblast growth factor receptor 1 c-splicing form), in the distal convoluted tubule to repress renal phosphorus reabsorption in the proximal tubule and suppress the renal synthesis of 1,25D. Klotho-FGFR1c is also expressed in the parathyroid glands.

Minireview: the play of proteins on the parathyroid hormone messenger ribonucleic Acid regulates its expression.

PTH regulates serum calcium and phosphate levels and bone strength. The parathyroid is unique in that the trigger for PTH secretion is a low extracellular calcium rather than high calcium as for other hormones. The parathyroid senses small changes in serum calcium through the seven-trans-membrane G protein-coupled calcium receptor to alter PTH secretion.

KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells.

Background: Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay.

Results: PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner.

The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism.

Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3' UTR region.

Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology.

1,25(OH)2D3 decreases parathyroid hormone (PTH) gene transcription through the vitamin D receptor (VDR). Total body VDR(-/-) mice have high PTH levels, hypocalcemia, hypophosphatemia, and bone malformations. To investigate PTH regulation by the VDR specifically in the parathyroid, we generated parathyroid-specific VDR knockout mice (PT-VDR(-/-)).

The calcium-sensing receptor regulates parathyroid hormone gene expression in transfected HEK293 cells.

Background: The parathyroid calcium receptor determines parathyroid hormone secretion and the response of parathyroid hormone gene expression to serum Ca2+ in the parathyroid gland. Serum Ca2+ regulates parathyroid hormone gene expression in vivo post-transcriptionally affecting parathyroid hormone mRNA stability through the interaction of trans-acting proteins to a defined cis element in the parathyroid hormone mRNA 3'-untranslated region. These parathyroid hormone mRNA binding proteins include AUF1 which stabilizes and KSRP which destabilizes the parathyroid hormone mRNA.

Vitamin D supplementation after renal transplantation: how much vitamin D should we prescribe?

Vitamin D deficiency is common in patients with chronic kidney disease after renal transplantation. Vitamin D, essential for mineral and bone metabolism, also has myriad beneficial autocrine effects on intact immune responses and defense against infection, as well as suppression of malignant changes. Supplementation with oral parental vitamin D could correct this problem.

Phosphate and the parathyroid.

The phosphate (Pi) retention in patients with chronic kidney disease leads to secondary hyperparathyroidism (2HPT). 2HPT is the physiological response of the parathyroid not only to Pi retention but also to decreased synthesis of 1,25(OH)(2) vitamin D, and the attendant hypocalcemia. 2HPT is characterized by increased PTH synthesis, secretion, and parathyroid cell proliferation.

Regulation of PTH mRNA stability by the calcimimetic R568 and the phosphorus binder lanthanum carbonate in CKD.

Secondary hyperparathyroidism is characterized by increased parathyroid hormone (PTH) mRNA stability that leads to increased PTH mRNA and serum PTH levels. PTH gene expression is reduced by the calcimimetic R568 and the oral phosphorus binder lanthanum carbonate (La). Changes in PTH mRNA stability are regulated by the binding of trans-acting stabilizing and destabilizing factors to a defined cis element in the PTH mRNA 3'-untranslated region (UTR).

Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion.

Purpose Of Review: The aim of this article is to describe the intriguing action of fibroblast growth factor 23 on the parathyroid.

Recent Findings: Fibroblast growth factor 23 inhibits renal phosphate reabsorption and calcitriol production. It is the principal phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization.

The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels.

Serum calcium and phosphate concentrations and experimental chronic kidney failure control parathyroid hormone (PTH) gene expression post-transcriptionally through regulated binding of the trans-acting proteins AUF1 and upstream of N-ras (Unr) to an AU-rich element (ARE) in PTH mRNA 3'-untranslated region (3'UTR). We show that the mRNA decay promoting K-homology splicing regulator protein (KSRP) binds to PTH mRNA in intact parathyroid glands and in transfected cells. This binding is decreased in glands from calcium-depleted or experimental chronic kidney failure rats in which PTH mRNA is more stable compared to parathyroid glands from control and phosphorus-depleted rats in which PTH mRNA is less stable.

The parathyroid is a target organ for FGF23 in rats.

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor.

The details bedevil DCOR.

Calcium-free oral phosphorus binders were heralded as a striking new development for patients with chronic kidney disease, promising a reduction in morbidity and mortality from cardiovascular disease. Sevelamer hydrochloride was the first such drug introduced to the market. Dialysis Clinical Outcomes Revisited (DCOR) is an outcomes study on the effect of sevelamer compared with calcium-based phosphorus binders in dialysis patients.

Regulation of parathyroid hormone mRNA stability by calcium, phosphate and uremia.

Purpose Of Review: This review focuses on the regulation of parathyroid hormone gene expression by dietary-induced hypocalcemia, hypophosphatemia and uremia. Understanding the mechanism by which calcium and phosphate regulate parathyroid hormone gene expression is important for both normal physiology and in pathological states, especially chronic kidney disease.

Recent Findings: Calcium and phosphate regulate parathyroid hormone secretion, gene expression and, if prolonged, parathyroid cell proliferation.

Lanthanum carbonate decreases PTH gene expression with no hepatotoxicity in uraemic rats.

Background: Lanthanum (La) carbonate is an effective phosphate-binder, used to reverse hyperphosphataemia due to chronic kidney disease. Some recent studies in rodents have cast safety uncertainties. The aims of this study were to examine the effects of La on parathyroid hormone (PTH) gene expression and hepatic toxicity.