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Frontiers in Endocrinology 2023The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D (1,25(OH)D). Early research efforts focused on... (Review)
Review
The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D (1,25(OH)D). Early research efforts focused on PTH and 1,25(OH)D and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)D and FGF23; the regulation of PTH by 1,25(OH)D, however, remains obscure. We review here our molecular understanding of how PTH induces expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)D. FGF23 and 1,25(OH)D, on the other hand, function by suppressing production of 1,25(OH)D. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of . PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied sites. The negative actions of both FGF23 and 1,25(OH)D appear to suppress expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at , the gene encoding the enzyme that degrades 1,25(OH)D, thereby contributing to the overall regulation of blood levels of 1,25(OH)D. Relative to PTH regulation, we summarize what is known of how 1,25(OH)D regulates PTH suppression. These studies suggest that it is not 1,25(OH)D that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an approach that furthers our understanding of the regulation of expression by PTH and 1,25(OH)D and provide the first evidence that P may act to induce expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.
Topics: Humans; Calcitriol; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Parathyroid Hormone; Kidney; Calcium
PubMed: 37441497
DOI: 10.3389/fendo.2023.1213361 -
Frontiers in Endocrinology 2022Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of... (Review)
Review
Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of sclerostin, an inhibitor of bone formation, and receptor activator of nuclear factor κ B ligand, an inducer of osteoblastic bone resorption. Osteocytes also govern phosphate homeostasis through the production of fibroblast growth factor 23 (FGF23), which lowers serum phosphate levels by increasing renal phosphate excretion and reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)D), an active metabolite of vitamin D. The production of FGF23 in osteocytes is regulated by various local and systemic factors. (), (), and function as local negative regulators of FGF23 production in osteocytes, and their inactivation causes the overproduction of FGF23 and hypophosphatemia. Sclerostin has been suggested to regulate the production of FGF23, which may link the two functions of osteocytes, namely, the control of bone mass and regulation of phosphate homeostasis. Systemic regulators of FGF23 production include 1,25(OH)D, phosphate, parathyroid hormone, insulin, iron, and inflammation. Therefore, the regulation of FGF23 in osteocytes is complex and multifactorial. Recent mouse studies have suggested that decreases in serum phosphate levels from youth to adulthood are caused by growth-related increases in FGF23 production by osteocytes, which are associated with the down-regulation of and .
Topics: Animals; Bone Density; Fibroblast Growth Factors; Humans; Mice; Osteocytes; Parathyroid Hormone; Phosphates
PubMed: 35909535
DOI: 10.3389/fendo.2022.967774 -
Archives of Endocrinology and Metabolism Nov 2022Hypoparathyroidism, despite the conventional therapy with calcium and active vitamin D, can lead to skeletal and nonskeletal abnormalities. Chronic hypoparathyroidism is... (Review)
Review
Hypoparathyroidism, despite the conventional therapy with calcium and active vitamin D, can lead to skeletal and nonskeletal abnormalities. Chronic hypoparathyroidism is associated with a significant reduction in bone remodeling, increases in areal and volumetric bone density, and improvement in trabecular microarchitecture and in trabecular bone score. Regardless of these advantages in bone mass and microarchitecture, recent data suggest an increased vertebral fracture risk in patients with nonsurgical hypoparathyroidism. Moreover, chronic hypoparathyroidism can lead to abnormalities in multiple organ systems, including the neurological, cardiovascular, renal, neuropsychiatric, ocular, and immune systems. Nephrocalcinosis, nephrolithiasis, and renal insufficiency, as well as decreased quality of life and cataracts, are common in patients with hypoparathyroidism. An increased incidence of hospitalization due to infections and a greater risk of cardiovascular diseases are observed in patients with hypoparathyroidism, particularly in those with nonsurgical disease. All these abnormalities may be because of the disease itself or complications of therapy. We herein reviewed the skeletal and nonskeletal consequences of hypoparathyroidism in patients conventionally managed with calcium and active vitamin D.
Topics: Humans; Calcium; Quality of Life; Hypoparathyroidism; Bone Density; Vitamin D; Parathyroid Hormone
PubMed: 36382753
DOI: 10.20945/2359-3997000000553 -
BMC Musculoskeletal Disorders Aug 2023The aim of this study was to compare serum vitamin D levels in girls with adolescent idiopathic scoliosis (AIS) and controls using meta-analysis methods. We searched... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this study was to compare serum vitamin D levels in girls with adolescent idiopathic scoliosis (AIS) and controls using meta-analysis methods. We searched Medline (via PubMed), Cochrane, Scopus, and Embase databases for studies evaluating outcomes in AIS, including patient age, body mass index, bone mineral density (BMD), and serum levels of parathyroid hormone (PTH), calcium, and phosphate, published between January 2000 and June 2020. We searched for studies that were limited to humans only. The inclusion criteria were a scoliosis study that measured vitamin D levels. We excluded duplicate publications such as review articles, case reports, and letters without original data. Two authors extracted data independently and resolved any discrepancies by consensus.
RESULTS
Eight comparative studies were identified. Demographic characteristics, bone density, serum levels of vitamin D, parathyroid hormone, and phosphate levels were not significantly different between AIS group and controls, except for serum calcium levels. The serum calcium levels were lower in AIS group than in the controls.
CONCLUSIONS
This review includes eight comparative studies reporting serum vitamin D and/or parathyroid hormone levels in AIS. Due to heterogeneity, a limited number of meta-analyses have shown a weak correlation between serum vitamin D levels and the incidence of AIS. Larger, multicenter studies are therefore needed to validate the results.
Topics: Female; Adolescent; Humans; Vitamin D; Calcium; Scoliosis; Vitamins; Kyphosis; Parathyroid Hormone; Phosphates
PubMed: 37644501
DOI: 10.1186/s12891-023-06793-0 -
Pediatric Nephrology (Berlin, Germany) Feb 2022The causes of hypercalcaemia in the neonate and infant are varied, and often distinct from those in older children and adults. Hypercalcaemia presents clinically with a... (Review)
Review
The causes of hypercalcaemia in the neonate and infant are varied, and often distinct from those in older children and adults. Hypercalcaemia presents clinically with a range of symptoms including failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures and hypotonia. When hypercalcaemia is suspected, an accurate diagnosis will require an evaluation of potential causes (e.g. family history) and assessment for physical features (such as dysmorphology, or subcutaneous fat deposits), as well as biochemical measurements, including total and ionised serum calcium, serum phosphate, creatinine and albumin, intact parathyroid hormone (PTH), vitamin D metabolites and urinary calcium, phosphate and creatinine. The causes of neonatal hypercalcaemia can be classified into high or low PTH disorders. Disorders associated with high serum PTH include neonatal severe hyperparathyroidism, familial hypocalciuric hypercalcaemia and Jansen's metaphyseal chondrodysplasia. Conditions associated with low serum PTH include idiopathic infantile hypercalcaemia, Williams-Beuren syndrome and inborn errors of metabolism, including hypophosphatasia. Maternal hypocalcaemia and dietary factors and several rare endocrine disorders can also influence neonatal serum calcium levels. This review will focus on the common causes of hypercalcaemia in neonates and young infants, considering maternal, dietary, and genetic causes of calcium dysregulation. The clinical presentation and treatment of patients with these disorders will be discussed.
Topics: Calcium; Creatinine; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Infant; Infant, Newborn; Parathyroid Hormone; Phosphates
PubMed: 33990852
DOI: 10.1007/s00467-021-05082-z -
Journal of the American Society of... Nov 2020
Topics: Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic
PubMed: 32931449
DOI: 10.1681/ASN.2020081182 -
Journal of Bone and Mineral Research :... Dec 2022
Topics: Humans; Hypoparathyroidism; Parathyroid Hormone
PubMed: 36375811
DOI: 10.1002/jbmr.4671 -
International Journal of Molecular... Apr 2020Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of... (Review)
Review
Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of the disease show significant differences between genders, with the majority of cases being reported in postmenopausal women. Due to this gender predilection, several studies have investigated the role of sex hormones in the pathogenesis of the disease and their potential use as targets for optimal and gender-specific management. Epigenetic mechanisms that regulate gene transcription may also contribute to these differences between genders. In this review, we outline what is currently known regarding the role of sex hormones and the recent data on the role of non-coding RNAs in the differences between genders in primary hyperparathyroidism due to sporadic parathyroid adenomas.
Topics: Disease Susceptibility; Epigenesis, Genetic; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Humans; Male; Parathyroid Hormone; Parathyroid Neoplasms; Prevalence; Sex Factors
PubMed: 32331456
DOI: 10.3390/ijms21082964 -
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