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Endocrinology and Metabolism (Seoul,... Jun 2024Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.... (Review)
Review
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.
Topics: Humans; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Parathyroid Hormone; Renal Insufficiency, Chronic; Hyperparathyroidism, Secondary; Animals
PubMed: 38752265
DOI: 10.3803/EnM.2024.1978 -
Journal of Bone and Mineral Research :... Dec 2022
Topics: Humans; Hypoparathyroidism; Parathyroid Hormone
PubMed: 36375811
DOI: 10.1002/jbmr.4671 -
Endocrinology and Metabolism Clinics of... Dec 2018Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and is due to insufficient levels of circulating parathyroid hormone. Hypoparathyroidism may be... (Review)
Review
Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and is due to insufficient levels of circulating parathyroid hormone. Hypoparathyroidism may be an isolated condition or a component of a complex syndrome. Although genetic disorders are not the most common cause of hypoparathyroidism, molecular analyses have identified a growing number of genes that when defective result in impaired formation of the parathyroid glands, disordered synthesis or secretion of parathyroid hormone, or postnatal destruction of the parathyroid glands.
Topics: Humans; Hypoparathyroidism; Parathyroid Diseases; Parathyroid Glands; Parathyroid Hormone
PubMed: 30390815
DOI: 10.1016/j.ecl.2018.07.007 -
Kidney International Dec 2016Circulating parathyroid hormone (PTH) shows a complex relationship with hard outcomes in subjects with chronic kidney disease (CKD). Moreover, intervention studies... (Review)
Review
Circulating parathyroid hormone (PTH) shows a complex relationship with hard outcomes in subjects with chronic kidney disease (CKD). Moreover, intervention studies directly targeting PTH failed to yield unequivocal results. Disturbed PTH metabolism, posttranslational modifications of PTH, and end-organ hyporesponsiveness to PTH may explain the poor performance of PTH as an outcome biomarker and precise target of therapy in the setting of CKD, at least in the gray middle target zone. PTH fragments accumulate in CKD patients and may exert effects that are distinct from, if not opposite to biointact (1-84)PTH. Posttranslational modification of PTH and especially oxidation may alter the interaction of PTH with its receptor. Its clinical relevance, however, remains a matter of ongoing debate. Less controversial is the issue of end-organ hyporesponsiveness to PTH. This phenomenon, formally referred to as PTH resistance, has long been recognized in CKD, but factors and mechanisms contributing to it remain poorly defined. Subsequent evidence identified downregulation of the PTH receptor and competing downstream signals as underlying pathophysiologic mechanisms. End-organ hyporesponsiveness to PTH in CKD, along with important analytical and biological variability, renders defining the PTH target range in CKD challenging. Although this may still be accomplished at the population level, it may prove to be very difficult at the individual level. This is a disillusioning thought in an era of personalized medicine. Parallel to the search of a functional and readily available assay quantifying PTH signaling tone or sensitivity, additional biomarkers (or a panel of biomarkers) should be formally evaluated.
Topics: Biomarkers; Humans; Parathyroid Hormone; Renal Insufficiency, Chronic
PubMed: 27653840
DOI: 10.1016/j.kint.2016.06.041 -
PloS One 2015Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer's disease and dementia. Abnormal parathyroid hormone (PTH)... (Review)
Review
BACKGROUND
Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer's disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not.
METHODS
We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies.
RESULTS
The twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains.
CONCLUSIONS
Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area.
Topics: Alzheimer Disease; Calcium; Cognition; Humans; Memory; Neurons; Parathyroid Hormone
PubMed: 26010883
DOI: 10.1371/journal.pone.0127574 -
Proceedings of the National Academy of... Jun 2023G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and...
G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.
Topics: Mice; Animals; Protein Binding; Vitamin D; Phosphates; Vitamins; Receptors, Parathyroid Hormone; Homeostasis; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Intracellular Signaling Peptides and Proteins
PubMed: 37252981
DOI: 10.1073/pnas.2220851120 -
International Journal of Molecular... Dec 2021Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate... (Review)
Review
Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors (lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.
Topics: Animals; Calcitonin; Calcium; Homeostasis; Humans; Life Style; Parathyroid Hormone; Phosphates
PubMed: 35008468
DOI: 10.3390/ijms23010044 -
Physiological Reports Apr 2022In the present study, we examined the systemic and direct effects of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) on duodenal, jejunal, and ileal...
In the present study, we examined the systemic and direct effects of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) on duodenal, jejunal, and ileal Mg absorption. The rats were injected with FGF-23 or PTH for 5 h before collecting the duodenum, jejunum, and ileum for Mg transport analysis in Ussing chambers. The duodenum, jejunum, and ileum were directly exposed to FGF-23, PTH, or FGF-23 plus PTH with or without cell signaling inhibitors for 150 min in Ussing chambers prior to performing the Mg transport study. The small intestinal tissues were also subjected to western blot analyses for FGF receptor (FGFR), PTH receptor (PTHR), Klotho, transient receptor potential melastatin 6 (TRPM6), and cyclin as well as the cystathionine β-synthase domain divalent metal cation transport mediator 4 (CNNM4) expression. The small intestine abundantly expressed FGFR and PTHR proteins, whereas, Klotho was not expressed in rat small intestine. Systemic PTH or FGF-23 injection significantly suppressed transcellular Mg transport in the duodenum and jejunum. Direct FGF-23-, PTH-, or FGF-23 plus PTH exposure also suppressed transcellular Mg absorption in the duodenum and jejunum. There was no additional inhibitory effect of PTH and FGF-23 on intestinal Mg absorption. The inhibitory effect of PTH, FGF-23, or FGF-23 plus PTH was abolished by Gö 6850. Systemic PTH- or FGF-23-injection significantly decreased membranous TRPM6 expression, but increased cytosolic CNNM4 expression in the duodenum, jejunum, and ileum. In the present study, we propose a novel magnesiotropic action of PTH and FGF-23 by modulating small intestinal Mg absorption.
Topics: Animals; Cation Transport Proteins; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Intestinal Absorption; Intestine, Small; Magnesium; Parathyroid Hormone; Rats
PubMed: 35385223
DOI: 10.14814/phy2.15247 -
American Journal of Physiology. Renal... Jun 2016The role of the kidney in calcium homeostasis has been reshaped from a classic view in which the kidney was regulated by systemic calcitropic hormones such as vitamin D3... (Review)
Review
The role of the kidney in calcium homeostasis has been reshaped from a classic view in which the kidney was regulated by systemic calcitropic hormones such as vitamin D3 or parathyroid hormone to an organ actively taking part in the regulation of calcium handling. With the identification of the intrinsic renal calcium-sensing receptor feedback system, the regulation of paracellular calcium transport involving claudins, and new paracrine regulators such as klotho, the kidney has emerged as a crucial modulator not only of calciuria but also of calcium homeostasis. This review summarizes recent molecular and endocrine contributors to renal calcium handling and highlights the tight link between calcium and sodium reabsorption in the kidney.
Topics: Animals; Calcium; Claudins; Feedback, Physiological; Homeostasis; Humans; Hypercalciuria; Kidney; Parathyroid Hormone; Receptors, Calcium-Sensing
PubMed: 27009338
DOI: 10.1152/ajprenal.00273.2015 -
Oncology Reports Oct 2016Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as... (Review)
Review
Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non‑mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N‑terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling.
Topics: Bone Neoplasms; Extracellular Matrix; Humans; Osteosarcoma; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Signal Transduction
PubMed: 27499459
DOI: 10.3892/or.2016.4986