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Frontiers in Endocrinology 2021Calcium is a key ion involved in cardiac and skeletal muscle contractility, nerve function, and skeletal structure. Global calcium balance is affected by parathyroid... (Review)
Review
Calcium is a key ion involved in cardiac and skeletal muscle contractility, nerve function, and skeletal structure. Global calcium balance is affected by parathyroid hormone and vitamin D, and calcium is shuttled between the extracellular space and the bone matrix compartment dynamically. The kidney plays an important role in whole-body calcium balance. Abnormalities in the kidney transport proteins alter the renal excretion of calcium. Various hormonal and regulatory pathways have evolved that regulate the renal handling of calcium to maintain the serum calcium within defined limits despite dynamic changes in dietary calcium intake. Dysregulation of renal calcium transport can occur pharmacologically, hormonally, and genetic mutations in key proteins in various nephron segments resulting in several disease processes. This review focuses on the regulation transport of calcium in the nephron. Genetic diseases affecting the renal handling of calcium that can potentially lead to changes in the serum calcium concentration are reviewed.
Topics: Calcium; Kidney; Parathyroid Hormone; Phosphates; Vitamin D
PubMed: 35299844
DOI: 10.3389/fendo.2021.762130 -
Physiological Reviews Jul 2016Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in... (Review)
Review
Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.
Topics: Animals; Bone Development; Bone Diseases; Cartilage; Humans; Mice; Parathyroid Hormone; Parathyroid Hormone-Related Protein
PubMed: 27142453
DOI: 10.1152/physrev.00031.2015 -
Cellular Signalling Jan 2018It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the... (Review)
Review
It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand. This is particularly true of arrestin pathway-selective 'biased' agonists. The type 1 parathyroid hormone receptor (PTHR) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTHR expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTHR signaling is highly sensitive to ligand structure, and PTH analogs that affect the selectivity/kinetics of G protein coupling or that engage arrestin-dependent signaling mechanisms without activating heterotrimeric G proteins have been identified. In vivo, intermittent administration of conventional PTH analogs accelerates the rate of osteoblastic bone formation, largely through known cAMP-dependent mechanisms. Paradoxically, both intermittent and continuous administration of an arrestin pathway-selective PTH analog, which in vivo would be expected to antagonize endogenous PTHR-cAMP signaling, also increases bone mass. Transcriptomic analysis of tissue from treated animals suggests that conventional and arrestin pathway-selective PTH1R ligands act in largely different ways, with the latter principally affecting pathways involved in the regulation of cell cycle, survival, and migration/cytoskeletal dynamics. Such multi-dimensional in vitro and in vivo analyses of ligand bias may provide insights into the physiological roles of non-canonical arrestin-mediated signaling pathways in vivo, and provide a conceptual framework for translating arrestin pathway-selective ligands into viable therapeutics.
Topics: Animals; Arrestins; Drug Design; Humans; In Vitro Techniques; Ligands; Models, Animal; Osteogenesis; Osteoporosis; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled
PubMed: 28495495
DOI: 10.1016/j.cellsig.2017.05.002 -
Physiological Research Dec 2023Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic... (Review)
Review
Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic MGD is more common and affects a similar patient profile as single gland parathyroid disease (SGD). The distinction between SGD and MGD is of great clinical importance, especially for the strategy of parathyroidectomy. Based on the limited knowledge available, MGD is likely to be a genetically heterogeneous disease resulting from the interaction of germline and somatic DNA mutations together with epigenetic alterations. Furthermore, these events may combine and occur independently in parathyroid tumors within the same individual with MGD. Gene expression profiling has shown that SGD and MGD may represent distinct entities in parathyroid tumorigenesis. We are waiting for studies to analyze exactly which genes are different in SGD and MGD in order to identify potential biomarkers that can distinguish between the two forms of the disease.
Topics: Humans; Hyperparathyroidism, Primary; Parathyroid Hormone; Retrospective Studies; Parathyroid Glands; Molecular Biology
PubMed: 38116772
DOI: 10.33549/physiolres.935253 -
Endocrinology and Metabolism (Seoul,... Mar 2020Since parathyroid hormone () was first isolated and its gene () was sequenced, only eight mutations have been discovered. The C18R mutation in , discovered in 1990, was... (Review)
Review
Since parathyroid hormone () was first isolated and its gene () was sequenced, only eight mutations have been discovered. The C18R mutation in , discovered in 1990, was the first to be reported. This autosomal dominant mutation induces endoplasmic reticulum stress and subsequent apoptosis in parathyroid cells. The next mutation, which was reported in 1992, is associated with exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the second exon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at the same residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somatic R83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, a heterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation was reported; this is the only reported hypoparathyroidism-causing mutation in the mature bioactive part of . In 2017, another heterozygous mutation, M14K, was detected. The discovery of these eight mutations in the gene has provided insights into its function and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detect other such mutations will help elucidate the functions of PTH in a more sophisticated manner.
Topics: Humans; Mutation; Parathyroid Diseases; Parathyroid Hormone
PubMed: 32207265
DOI: 10.3803/EnM.2020.35.1.64 -
Journal of Bone and Mineral Research :... Jun 2021The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and... (Clinical Trial)
Clinical Trial
The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Adult; Calcitriol; Calcium; Humans; Hypoparathyroidism; Parathyroid Hormone; Quality of Life; Teriparatide
PubMed: 33666947
DOI: 10.1002/jbmr.4274 -
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi =... Oct 2021Parathyroid hormone (PTH) exerts multiple effects such as regulating bone remodeling, promoting angiogenesis, etc., and it is an active factor with great application... (Review)
Review
Parathyroid hormone (PTH) exerts multiple effects such as regulating bone remodeling, promoting angiogenesis, etc., and it is an active factor with great application potential for bone repair. In recent years, with the development of scaffold material loading strategies and parathyroid hormone-related peptides (PTHrPs), in situ loading of PTH or PTHrPs on scaffold materials to promote bone defect healing gradually becomes possible. Based on the current status and challenges of intermittent PTH (iPTH) for bone tissue engineering, the review summarizes the in-situ application strategies of PTH and the construction of PTHrPs as well as current problems and further directions in this field, with a view to propel the clinical application of scaffold materials loaded with PTH or PTHrPs .
Topics: Bone and Bones; Parathyroid Hormone; Tissue Engineering; Tissue Scaffolds; Wound Healing
PubMed: 34713672
DOI: 10.7507/1001-5515.202104045 -
Journal of Clinical Laboratory Analysis Jun 2021Several pre-analytical factors can affect the measurement of intact Parathyroid Hormone (IPTH). In this study, we have investigated the effects of using different types...
BACKGROUND
Several pre-analytical factors can affect the measurement of intact Parathyroid Hormone (IPTH). In this study, we have investigated the effects of using different types of tubes, time elapsed before separation, and storage conditions over time on the measured values of IPTH.
METHOD
Blood samples from 30 subjects were collected into plain, SST, and EDTA tubes. All serum and plasma were separated immediately (first set) and after 2 hrs delay (second set). The first set of samples were aliquoted and stored at RT (25°C), at fridge (4°C), and freezer (-20°C). IPTH was measured in all the stored aliquots at 2,4, and 8 days after collection using Architect analyzer.
RESULTS
Paired T test and ANOVA repeated measures showed no significant difference between IPTH levels in all tubes. The second set of serum and plasma were significantly lower (3.8% and 7.4%, p < 0.001, respectively) when compared to samples measured initially. Serum samples stored at RT were significantly lower (by 45%,59%, and 77%) on days 2,4, and 8 when compared to the initial time (p < 0.001 in all cases). Plasma samples stored at RT, were significantly lower on day 8 after collection, by 30.8% (p < 0.001). These differences would be clinically important.
CONCLUSION
Plasma IPTH can be stored at RT for up to four days. Both plasma and serum IPTH are not affected by a delay in the separation of up to two h and they can be stored for up to 8 days in a fridge or freezer without any clinically significant changes in their values.
Topics: Adult; Blood Preservation; Blood Specimen Collection; Female; Humans; Male; Parathyroid Hormone; Reproducibility of Results; Time Factors
PubMed: 33792964
DOI: 10.1002/jcla.23771 -
Clinical Chemistry and Laboratory... Jun 2017Different imaging tools, circulating endocrine markers, and fine-needle aspiration (FNA) cytology are of great importance in the diagnosis and follow-up of different... (Review)
Review
Different imaging tools, circulating endocrine markers, and fine-needle aspiration (FNA) cytology are of great importance in the diagnosis and follow-up of different thyroid and parathyroid diseases. Sometimes, however, they are conflicting or inconclusive: interestingly, measuring endocrine markers (i.e. thyroglobulin, calcitonin, parathyroid hormone) in fluids from FNA proved to be a very useful complementary diagnostic tool in such cases. The determination of endocrine markers in fluids other than serum/plasma has been developed in the last years. Although studies have reported overall satisfactory results, a good standardization of procedures has not yet been reached, and further efforts should be made in order to better define pre-analytical, analytical, and post-analytical aspects. Here we reviewed critically the literature on the measurement of FNA endocrine markers, focusing on laboratory issues, such as preparation of the sample, choice of solution, and technical features of determination of these markers. Indeed, information for use of FNA-Tg, FNA-CT, and FNA-PTH in clinical practice was also provided.
Topics: Biopsy, Fine-Needle; Calcitonin; Clinical Chemistry Tests; Humans; Parathyroid Hormone; Thyroglobulin
PubMed: 27802177
DOI: 10.1515/cclm-2016-0543 -
Frontiers in Endocrinology 2023
Topics: Parathyroid Hormone; Calcium; Parathyroidectomy; Calcium, Dietary
PubMed: 37188053
DOI: 10.3389/fendo.2023.1199056