J Bone Miner Res. Effect of phosphate on parathyroid hormone secretion in vivo. Favus MJ, Goltzman D. Regulation of calcium and magnesium. In: Rosen JF, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Washington: The Sheridan Press; Dietary reference intakes: calcium, phosphorus, magnesium, vitamin D, and fluoride.
Washington: National Academy Press; Control of hydroxycholecalciferol metabolism by parathyroid glands. Acute biochemical variations induced by two different calcium salts in healthy perimenopausal women.
High phosphorus intake only slightly affects serum minerals, urinary pyridinium crosslinks and renal function in young women. Eur J Clin Nutr. Guillemant J, Guillemant S.
Comparison of the suppressive effect of two doses mg vs mg of oral calcium on parathyroid hormone secretion and on urinary cyclic AMP. Mineral water as a source of dietary calcium: acute effects on parathyroid function and bone resorptionin young men. Age-related effect of a single oral dose of calcium on parathyroid function:relationship with vitamin D status.
Dose dependency of calcium absorption: a comparison of calcium carbonate and calcium citrate. Heaney RP. Dietary protein and phosphorus do not affect calcium absorption. Calcium effects on phosphorus absorption:Implications for theprevention and co-therapy of osteoporosis.
J Am Coll Nutr. CrossRef Google Scholar. Effects of nitrogen, phosphorus, and caffeine on calcium balance in women. J Lab Clin Med. Urinary calcium and calcium balance in young men as affected by level of protein and phosphorus intake. Calcium regulating hormones after oral and intravenous calcium administration. Circadian rhythm and pulsatility of parathyroid hormone secretion in man.
Clin Endocrinol Oxf. Predictors of calciumretention in adolescent boys. Oral calcium suppresses biochemical markers of bone resorption in normal men.
High dietary phosphate intake reduces bone strength in the growing rat skeleton. Acute effects of different phosphorus sources on calcium and bone metabolism in young women: a whole foods approach. Calcif Tissue Intl. Also, FGF23 could decrease the phosphate levels through reducing the renal phosphate reabsorption and intestinal absorption by inhibiting the production of 1,25 OH 2 D Shimada et al. Based on the detailed understanding of calcium and phosphorus metabolism, we could better explore many genetic or non-hereditary factors that will cause disorders of calcium and phosphorus metabolism via impairing the functions of organs or concentrations of the related hormones, respectively.
For example, hyperparathyroidism and hypoparathyroidism could induce the imbalance of calcium and phosphorus via influencing the levels of PTH. Additionally, malignancy is also a common cause for disorders of calcium and phosphorus metabolism via direct invasion of bone in Local Osteolytic Hypercalcemia LOH , enhancing the flow of parathyroid hormone-related protein PTHrP , which has the similar function with PTH, or increased synthesis of 1,25 OH 2 D in various lymphoid tumors Guise et al.
Acute or chronic kidney disease could disrupt the phosphorus balance through phosphate excretion failure and impair calcium metabolism through a loss of vitamin synthesis capacity. Although there are some clinical methods identified to diagnose the disorders of calcium and phosphorus metabolism, including blood tests, bone density scan, radiography, and bone biopsy, they are not universally applicable due to great trauma, high price, and low specificity Nickolas and Jamal, Therefore, it is necessary to explore novel diagnostic biomarkers valuable to detect this disease.
For the in-depth understanding of the disorders of calcium and phosphorus metabolism, omics help a lot, especially proteomics and metabolomics. Proteomics generally refers to analysis of a wide range of proteins, which vary with time and different states the organism undergoes Anderson and Anderson, ; Blackstock and Weir, While metabolomics, an emerging technology to study metabolites, the small molecule substrates, provides a direct readout of organism state Nicholson, An essential focus of proteomics and metabolomics is the identification of novel biomarkers, which could detect disease quickly.
For instance, immunoglobulin heavy constant alpha 2 was identified by Kang et al. Another focus is the elucidation of pathogenesis and the discovery of personalized and precision treatment relies on the molecular characteristics associated with a disease Vaidyanathan, For example, Jamshidi et al. We will also provide current examples of proteomics and metabolomics applications in the disorders of calcium and phosphorus metabolism at the end of this review.
Calcium is the most abundant ion in the body, which plays a pivotal role in cell membrane function and intracellular signaling. Calcium in extracellular fluids, intracellular fluids, and bone are balanced by the calcium absorbed in the diet at the small intestine. Calcium exchange between extracellular fluids and bone is an essential dynamic part of bone remodeling via a rapidly exchangeable pool.
Urinary excretion is also involved in achieving the calcium homeostasis Parfitt, a,b ; Kumar, Calcium in extracellular fluids is present in three fractions.
The remaining, the most critical form of calcium in extracellular fluids exists as an active free ionized fraction, which determines the physiological effect of calcium Bushinsky and Monk, , because it interacts directly with cell membranes, with calcium channels, and with the calcium-sensing receptor CaSR. Calcium-sensing receptor is abundantly in the parathyroid cells, where it represents the molecular mechanism by which parathyroid cells detect a tiny reduction of ionized calcium concentration and modulate the rapid release of PTH accordingly Brown et al.
Briefly, decreased plasma calcium concentration will inactivate CaSR, leading to increased flow of PTH, which has a direct effect on the renal calcium reabsorption and bone absorption through the interaction with the receptorPTH1R van Abel et al. Note that although the 1,25 OH 2 D manufacture in the kidney could be promoted by PTH, itself plays an inhibitory role in the synthesis and secretion of PTH, which might be explained by a feedback loop Demay et al.
Conversely, when the calcium levels rise, the thyroid gland will increase the flow of calcitonin, another polypeptide hormone, which could reduce the secretion of PTH, resulting in the opposite direction Talmage et al.
The paracellular route depends on the concentration gradient of calcium along the tight junction in the intestinal epithelium. While, the active pathway for intestinal calcium absorption is subject to rather strict transcriptional control of 1,25 OH 2 D, which represents a pivotal adaptive mechanism under calcium deficiency.
Once absorbed, the transcellular movement of calcium in the cytosol to the opposite side is completed under the help of calbindin, a vitamin D-dependent protein. Mittermeier et al. The paracellular route might also be mediated by 1,25 OH 2 D partly, but it remains unknown Chirayath et al. Note that PTH has a more significant influence on the urinary excretion of phosphate ions than calcium Blaine et al. Since phosphates could combine with calcium ions to form insoluble complexes, more phosphate removal will ultimately raise the serum ionized calcium levels.
It is worth mentioning that the kidney could also influence the plasma calcium concentration through processing vitamin D into calcitriol under the influence of high PTH levels.
It is a complicated and dynamic tissue mediated by bone-absorptive osteoclasts and bone-forming osteoblasts Martin and Sims, ; Florencio-Silva et al.
Phosphorus is critical for many normal biological activities, including muscle contraction, cell signaling, and stabilization of membranes. Plasma phosphorus balance is the result of phosphate uptake at intestine and reabsorption in the kidney. Intestinal phosphorus absorption occurs predominantly in the passive paracellular pathway through the luminal concentration of phosphorus.
A small energy-dependent transcellular route occurs through NaPi-IIb across the apical brush-border membrane. There is a variety of hormones that influence the renal handling of phosphorus through NaPi-II cotransporters. Fibroblast growth factor 23 FGF23 , another critical hormone that reduces the phosphorus levels, also has been shown to decrease NaPi-II cotransporters expression in the proximal tubule Schiavi, ; Razzaque and Lanske, ; Farrow et al.
Under average conditions, adults have a net skeletal phosphorus balance close to zero through adjusting the amount of phosphate absorption and urinary excretion.
Several essential factors, including phosphatonins, the phosphate-regulating genes associated with endopeptidase PHEX , etc. However, the comprehensive understanding of phosphorus metabolism in bone still remains elusive, which needs further investigation. In conclusion, maintenance of calcium and phosphate ions within narrow range tightly relies on three organs: intestine, kidney, and bone.
Among them, PTH maintains calcium and phosphorus homeostasis by 1 enhancing the intestinal calcium and phosphate absorption through promoting the manufacture of 1,25 OH 2 D; 2 increasing phosphorus excretion through its internalization effect on NaPi-II cotransporters and interaction with PTH1R in the kidney; 3 increasing bone absorption. The most important function of vitamin D is to promote the absorption of calcium and phosphorus at intestine.
FGF23 could reduce phosphorus levels by inhibitory role on NaPi-II cotransporters in the kidney and promote the phosphorus uptake into the bone indirectly. Figure 1. Calcium and phosphorus homeostasis. Regulation of calcium and phosphorus homeostasis tightly relies on a variety of concerted actions of three target organs: intestine, kidney and bone, whose functions are principally regulated by a panel of hormones, including PTH, vitamin D, FGF23 and various factors.
Tiny changes in calcium could be sensed by CaSR and Calcitonin located in the thyroid gland, thereby modulating the flow of PTH accordingly. FGF23, another critical hormone that promote phosphorus urinary excretion, has been shown to decrease NaPi-II cotransporters expression in the proximal tubule. Hypercalcemia occurs in approximately 1 in among the general adult population Waters, Malignancy and hyperparathyroidism are the two most common causes Bilezikian and Silverberg, ; Stewart, In patients with LOH, the hypercalcemia results from a variety of osteoclast activating factors, which are responsible for the significant increase in osteoclast absorption Roodman, , while HHM is caused by considerable flow of parathyroid hormone-related protein PTHrP derived from malignant cells Guise et al.
Although PTHrP bears similarity to PTH only in the initial eight amino acids, its capacity to bind to the PTH receptor is basically the same, which promotes bone absorption and increases renal reabsorption of calcium Stewart et al. Hyperparathyroidism could also be classified into three categories: 1 primary hyperparathyroidism, which is primarily caused by adenomas of parathyroid glands; 2 secondary hyperparathyroidism, which is caused by resultant hyperplasia of parathyroid glands in response to hypocalcemia; 3 tertiary hyperparathyroidism, a term used to describe progressive stage of secondary hyperparathyroidism along with unresponsive flow of PTH.
Patients with hyperparathyroidism will show increased synthesis of 1,25 OH 2 D as a subsequent result of the elevation of PTH levels. Therefore, the promotion of renal reabsorption of calcium by PTH and increased osteoclast and intestinal calcium absorption by 1,25 OH 2 D lead to the occurrence of hypercalcemia.
Also, patients with Familial hypocalciuric hypercalcemia FHH , a rare inherited disease with mutation in CaSR, could also result in hypercalcemia because the inactive CaSR in the parathyroid gland will lead to a slight elevation of PTH, similar to the hyperparathyroidism discussed above Carroll and Schade, Furthermore, sarcoidosis, a multisystem granulomatous disorder, the cause of which is still not elucidated, could also result in hypercalcemia because of the elevated levels of 1,25 OH 2 D Iannuzzi et al.
Contrary to hyperparathyroidism, hypoparathyroidism, which refers to the impaired secretion of PTH due to the irreversible parathyroidectomy, radiation damage, and congenital disabilities, is the leading cause of chronic hypocalcemia. A similar disease term called pseudohypoparathyroidism PsHP , showing resistant to PTH, is also characterized by hypocalcemia.
In addition, the lack of vitamin D caused by UV exposure deficiency or kidney dysfunction, could also result in hypocalcemia Cooper and Gittoes, Because the organs that regulate phosphorus balance are principally the intestine, kidney, and some other tissues, hyperphosphatemia will occur when intestinal absorption rises, renal excretion in acute or chronic kidney disease reduces, or tissue release of phosphorus to extracellular fluids enhances.
It is noteworthy that in addition to the hypocalcemia resulting from kidney disease because of impaired vitamin D synthesis, hyperphosphatemia could also occur in chronic kidney disease CKD caused by the phosphorus excretion failure. Since phosphates could combine with calcium ions to form insoluble complexes, hyperphosphatemia-induced calcium deposits in the soft tissues will ultimately lead to abnormalities in bone morphology such as bone mineralization and calcification of blood vessels Fukagawa et al.
Hypoparathyroidism-related hyperphosphatemia refers to the low levels of PTH, which typically promotes phosphate excretion. Therefore, PTH insufficiency could result in more phosphate remaining in the blood.
Also, increased tissue release of phosphorus could also occur in tumor lysis syndrome, rhabdomyolysis, hemolysis, hyperthermia, acute leukemia, etc.
Voelkl et al. It could be divided into nutritional rickets and hereditary rickets due to different pathogenesis. Hereditary rickets could be classified into two categories due to different types of gene variations: 1 vitamin D-dependent rickets Miller, ; and 2 hereditary hypophosphatemic rickets HP Beck-Nielsen et al.
Therefore, its typical biochemical characteristics are hypocalcemia and hypophosphatemia caused by vitamin D deficiency. Hereditary hypophosphatemic rickets HR is a rare group of renal phosphate wasting disorders. Hypophosphatemia and average calcium concentration are their typical biochemical characteristics. It is a type of hereditary rickets caused by the variations in phosphoproteins or cotransporters, which are necessary for renal phosphate reabsorption Guven et al.
So far, a panel of genetic causes has been identified. Although these two types could be distinguished by FGF23 concentration easily, the diseases within the group need to be differentiated by further molecular testing. Other rare genetic diseases involving osteoglophonic dysplasia, McCune—Albright syndrome, Raine syndrome, opsismodysplasia, etc. In addition to changes in FGF23 levels, cotransporters and PTH receptor variations could also induce hypophosphatemia via disrupted phosphorus reabsorption metabolism.
In addition to hereditary rickets, nutritional rickets is also a serious global public health problem, which refers to abnormal bone mineralization caused by vitamin D deficiency. The classification of disorders of calcium and phosphorus metabolism is summarized in Table 1. Although all proteins are based on DNA, post translational modifications render gene analysis alone is impossible to define the abundance of proteins.
The proteome consists of all proteins present in particular cell types or tissues, while the metabolome consists of small molecules known as metabolites Blackstock and Weir, ; Hollywood et al. They are technologies that comprehensively characterize the protein and metabolic levels of cells or organisms to study the roles of proteins and the metabolic profiles in biological and pathological systems Nicholson et al.
Therefore, they are promising approaches to identify biomarkers or unmask perturbations and signal pathways associated with disease through available biological samples, such as urine Want et al. Qiu et al. Also, a rapidly growing body of proteomics and metabolomics related work has promoted the development of precision medicine and has been widely concerned Suhre et al. To illustrate the current status of the applications of proteomics and metabolomics in disorders of calcium and phosphorus metabolism, we discuss here the advances that used these technologies to investigate novel biomarkers and disturbed pathways related with this disease.
To unveil the pathophysiology of PHPT, molecular details about parathyroid hyperplasia and adenoma, two similar causes contributing to the PHPT, must be revealed. Therefore, Akpinar et al.
Forty novel dysregulated proteins of interest were identified, of which 14 were up-regulated in hyperplasia and 26 were overexpressed in adenoma. It is worth mentioning that most of the up-regulated proteins in hyperplasia identified are mitochondrial proteins, involving cytochrome b-c1 complex subunit 1, enoyl-CoA hydratase, 60 kDa heat shock protein, etc.
Although this research could not create a biomarker panel, the changes in mitochondrial proteins expression yield important direction for future studies to differentiate parathyroid hyperplasia and adenoma, which remained a significant challenge to dissolve Akpinar et al. Varshney et al. Although functional categorization of dysregulated proteins did not focus on a certain signaling, the services of the identified proteins associate with a massive number of pathways, including the regulation of programed cell death, transcription, and signal transduction, etc.
Among them, ATP synthase subunit d protein is also reported in the research by Akpinar et al. However, majority of the identified proteins are different with the earlier study by Giusti et al. Caucasian , that needs further validation. Therefore, the characterized proteins might provide new directions for the in-depth exploration of molecular details of the disease and novel therapeutic options that target at the differentially expressed proteins Varshney et al.
On the one hand, evidence shows that parathyroid adenomas might consist of chief cells, oxyphilic cells, or a mixture of both cells Williams, To differentiate different cell types within parathyroid adenomas, Lu et al. Intriguingly, lower expression of nuclear receptor TR4 was reported in oxyphilic cells compared to chief cells. In addition, compared to cytoplasm and nuclei subcellular location of TR4 in normal parathyroid, it mainly localized in the nuclei of adenomas, implying different roles of TR4 in adenomas that remains elusive, which needs further investigation.
On the other hand, PHPT could also be classified into two different groups based on their relative responsiveness to ambient calcium. Koh et al. Notably, based on the results of studies by Akpinar et al. Hence, the results suggest that the different PHPT clinical presentation, provenance and outcome might be caused by different molecular basis, which remains unknown Koh et al. A single gland disease SGD , which is caused by a single parathyroid adenoma, and multiglandular disease MGD , which is recognized with multiple adenomas or multiglandular hyperplasia, both could result in PHPT; however, there are no biomarkers available to differentiate these two types.
Therefore, Battini et al. For instance, compared with MGD, elevated levels of succinate and fumarate were observed in SGD, which involved in the tricarboxylic acid cycle, while a higher expression of glutamate, GSH, and ascorbate serving as antioxidants in MGD. Calcium absorption may be decreased by high dietary levels of phosphate, oxalate in rhubarb and certain leafy green vegetables , or phytate compounds in fiber.
Too much protein in the diet may increase the amount of calcium excreted in the urine and decrease the amount available for building bones. You may be trying to access this site from a secured browser on the server. Please enable scripts and reload this page. Turn on more accessible mode. Turn off more accessible mode. Skip Ribbon Commands. Skip to main content. Turn off Animations. Turn on Animations. The metabolic paths of the three elements are by no means wholly parallel, even though the major part of the body content of each is found in the same tissue.
Whereas 99 per cent of body calcium is found in the skeletal structures, bones and teeth, both phosphorus and magnesium are important constituents of soft tissue also. The small amount of calcium not in bone is a component of extracellular fluid; magnesium and phosphate, on the other hand, are components of intracellular fluids, and the phosphate radical appears to be essential in an ever increasing number of metabolic reactions. Milk and its derivatives, such as cheese and ice cream, are the chief sources of calcium in the diet.
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