Calcium Metabolism Or Calcium Homeostasis Health Essay

Most of us are progressively cognizant of the demand for Ca in the diet as an indispensable factor for our wellness and length of service. But we are cognizant that non all signifiers of Ca are the same? When our wellness physicians recommend that we go to the shop and acquire some over the counter Ca tablets and take two a twenty-four hours, they are truly cognizant of how small of the Ca is bioavailable to the cells in our organic structures? Are they skilled in biochemical Ca soaking up and they know how much Ca we consume in these tablet signifiers fattens sewer in America, and non plenty to make full our organic structure ‘s critical demand for Ca? In this short article, I will educate you merely a small spot about how our Ca is absorbed and how best to acquire calcium of import for proper metamorphosis and good wellness.
The serum Ca is closely regulated with a normal entire Ca of 2,2-2,6 mmol / L ( 9-10.5 milligram / deciliter ) and a normal ionised Ca 1,1-1,4 mmol / L ( 4.5-5.6 milligram / deciliter ) . The entire Ca varies with the degree of serum albumen, a protein that Ca is bound. Calcium Metabolism Or Calcium Homeostasis Health Essay. The biological consequence of Ca is determined by the sum of ionised Ca instead than entire Ca. Ionized Ca do non change with the albumen degree, and therefore it is interesting to mensurate the ionised Ca in the blood when the serum albumen is non within the normal, or when a Ca upset is suspected despite a normal entire Ca degree.
Calcium is a mineral that is stored in castanetss. Almost all the Ca in the organic structure is stored in bone. But a little per centum ( around 1 % ) circulates in the blood and other organic structure fluids, or is contained in our cells. This is needed ( Keeping healthy castanetss and dentitions, blood curdling, and normal map of the encephalon and spinal cord ( cardinal nervous system ) and maintain our musculuss working ) If your blood Ca degree gets excessively high or excessively low can be unsafe. Have excessively much Ca in the blood called hypercalcaemia Hypercalcemia of malignant neoplastic disease can be a serious job for some people. Not holding adequate Ca is called hypocalcaemia.
Our diet provides us with Ca. The nutrients highest in Ca include ( dairy merchandises like eggs, milk, butter and cheese – that ‘s where most of our Ca from green veggies as Brassica oleracea italica, Spinacia oleracea and beans, nuts ) Our organic structures absorb Ca from nutrient we eat through the liner of the bowel. Calcium is broken down before it is stored in the castanetss. The organic structure controls the sum of Ca in the blood really carefully. When blood Ca fall excessively low, the castanetss release Ca in the blood. The sum of Ca absorbed from nutrient in the bowel besides increases. And the kidneys to acquire rid of the less Ca in the piss. If blood Ca degrees get excessively high, the opposite happens.
There are 3 endocrines in the organic structure that plays an of import function in this complex control system. These are ( of parathyroid endocrine ( PTH ) – of prathyroid secretory organs, vitamin D, calcitonin
These endocrines help to maintain the right balance of Ca in the blood.
If this balance is disquieted, the sum of Ca in the blood gets excessively high ( hypercalcaemia ) and cause serious problems.The chief causes of hypercalcaemia are ( excessively much Ca leaking from bone to blood, your kidneys are non able to acquire rid of extra Ca and pickings in excessively much Ca from nutrient we eat )
What Helps Your Body With Calcium Absorption?
1. Your organic structure needs stomach acid for good soaking up of Ca. If you have of all time had pyrosis or dyspepsia, you know what we mean by stomach acid. When you eat, make full your tummy with strong acids to interrupt down nutrient. These acids are indispensable for Ca soaking up. Calcium Metabolism Or Calcium Homeostasis Health Essay.
2. Calcium soaking up is non as effectual if you have a vitamin lack. Vitamin D is of import for the organic structure ‘s soaking up of Ca, and research workers have shown that if you do non acquire adequate vitamin D in your diet, you can acquire osteoporosis.
Calcium soaking up is the sum the organic structure from the GI piece of land into the organic structure ‘s circulation. Calcium soaking up may be affected by the organic structure ‘s position of Ca and vitamin D, age, gestation and works substances in your diet.

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The sum of Ca consumed at one clip can besides impact soaking up. In other words, Ca soaking up decreases when the sum of Ca increases the ingestion of a repast. Thus the spread of ingestion of Ca throughout your twenty-four hours is best.
Other factors play of import functions in Ca soaking up are:
Age: Net Ca soaking up can be every bit high as 60 % in babies and immature kids, when the organic structure needs Ca to construct strong castanetss. Absorption decreases easy to 15-20 % in maturity and even more as one ages. Since Ca soaking up decreases with age, recommendations for consumption of Ca is higher for grownups aged 51 and over.
Vitamin D improves soaking up of Ca. Your organic structure can obtain vitamin D from nutrient and it can besides do vitamin D when tegument is exposed to sunlight. Consequently, sufficient consumption of vitamin D from nutrient and the Sun is of import.
Fiber, peculiarly from wheat bran, can besides forestall Ca soaking up because of its content of phytate. By contrast, the consequence of fibre on Ca soaking up is more of a job for people with low Ca consumption. The mean American tends to devour less fiber per twenty-four hours than the degree that would be needed to impact Ca soaking up.
Calcium elimination refers to the sum of Ca excreted from the organic structure in urine, fecal matters and perspiration. Calcium in the piss can be affected by many factors:
aˆ? Typically, dietetic Na and protein addition Ca elimination as the sum of consumption increased. But if a high-protein, high Na nutrient besides contains Ca, this may assist to countervail the loss of Ca. aˆ? Increase dietetic consumption of K in the presence of a high Na diet can lend to reduced elimination of Ca, particularly in postmenopausal adult females. Or cut down the consumption of Na. aˆ? Caffeine has a little consequence on Ca soaking up. aˆ? Alcohol can impact Ca position by cut downing the intestine.
Effecter variety meats
Beginnings
Approximately 25 mmol of Ca in the organic structure of a normal diet. It may be less if the diet is low in milk and milk merchandises or other calcium-containing nutrients ( such as some signifier of fish, or calcium-rich H2O, Ca of leafy green veggies is ill absorbed ) . Ofthis, about 40 % ( 10 mmol ) absorbed in the bowel, and 5 mmol leaves the organic structure with fecal matters, sacking 5 mmol Ca per twenty-four hours.
Elimination
The kidney excretes 250 mmol a twenty-four hours in the pro-urine, and resorbs 245 mmol, taking to a net loss in the piss of 5 mmol / l.Calcium Metabolism Or Calcium Homeostasis Health Essay.  In add-on, the kidney processes vitamin D ofcalcitriol, the active signifier that is most effectual in assisting the intestine. Both procedures are stimulated by parathyroid endocrine.
Role of bone
The Ca flow into and out of the bone is impersonal, is about 5 mmol opted for a twenty-four hours. Ben serves as an of import storage site for Ca, because it contains 99 % of entire organic structure Ca. Calcium release from bone is regulated by parathyroid endocrine. Calcitonin stimulates the debut of Ca in castanetss, although this procedure is mostly independent of calcitonin. Low Ca consumption may besides be a hazard factor for developing osteoporosis. In a meta-analysis, the writers found that merely two of the 52 surveies they reviewed showed that Ca consumption does non advance a better balance of bone. With a better balance of bone, the hazard of osteoporosis is reduced.
Interaction with other chemicals
Potential positive interactions
aˆ? Vitamin D is an of import co-factor in the enteric soaking up of Ca, because it increases the figure of calcium channel proteins involved in Ca soaking up through the apical membrane of enterocytes in the little bowel. It besides promotes re-absorption of Ca in the kidneys. aˆ? Boron
Potential negative interactions
Sodium, Phytic acid, Oxalic acid, Caffeine, Cortisol.
Low pH nutrient and proteins ( the latter promotes stomachic acid )
Regulative variety meats
Chiefly calcium-regulated by action of 1,25-OH vitamin D3, parathyroid endocrine and calcitonin and direct exchange with bone. Plasma Ca degrees are regulated by hormonal and non-hormonal mechanisms. After consumption of big sums of Ca, such as in a glass of milk, the short-run control to forestall the added Ca in serum is soaking up of bone tissue. After about an hr, PTH is released and non top out for approximately 8 hours. The PTH, over clip, a extremely powerful regulator of plasma Ca, and regulate the transition of vitamin D to its active signifier in the kidneys. Parathyroid glands behind the thyroid secretory organ and bring forth parathyroid endocrine in response to low Ca degrees.
The parafollicular cells in the thyroid produce calcitonin in response to high Ca degrees, but its significance is much smaller than that of PTH.
Pathology
Hypocalcemia and hypercalcaemia are both serious medical jobs.
Nephritic osteodystrophy is a effect of chronic nephritic failure associated with Ca metamorphosis.
Osteoporosis and osteomalacia have been linked to calcium metamorphosis upsets.
Hypercalcemia
Hypercalcemia is a disease that most frequently due to malignance or primary hyperparathyroidism. Other causes of elevated Ca are less common and normally non considered until malignance and parathyroid disease excluded.
Hypercalcemic crisis is non a precise definition, but marked lift of serum Ca, normally more than 14 mg / deciliter, is associated with acute marks and symptoms of hypercalcaemia. Treatment of elevated Ca in the blood can decide the crisis.
The mention figure of serum Ca is 8,7-10,4 milligram / deciliter, with somewhat higher among kids. Approximately 40 % of Ca is bound to proteins, chiefly albumin, while 50 % are ionized and physiologically active signifier. The staying 10 % being complexed with anions. Calcium Metabolism Or Calcium Homeostasis Health Essay.
Why people with malignant neoplastic disease get hypercalcemia
Between 10 and 20 of 100 patients with malignant neoplastic disease ( 10 to 20 % ) developed hypercalcaemia. This occurs most frequently in advanced phases of malignant neoplastic disease but it can go on in people with earlier phases. Cancer makes Ca leak into the blood from your legs, so that degrees in the blood becomes excessively high. Cancer can besides impact the sum of Ca that your kidneys can acquire rid of. If you have 2nd leg Aries, damaged countries of bone can let go of Ca in the blood. Dehydration from being vomit a batch or have diarrhea besides can increase Ca degrees. It is really of import that you do something about it. If left untreated, hypercalcaemia can do you more and more drowsy until you sleep most of the clip. If you are still non treated, can you travel into a coma and finally decease. The malignant neoplastic diseases most normally associated with hypercalcaemia are Multiple myeloma – about half of all people with myeloma have hypercalcemia at some point during their unwellness, chest malignant neoplastic disease, squamous cell lung malignant neoplastic disease, kidney malignant neoplastic disease, caput and cervix malignant neoplastic disease, prostate malignant neoplastic disease. Although uncommon, hypercalcaemia can impact people with other malignant neoplastic diseases.
Symptoms of hypercalcemia
It is non ever easy for a physician to detect that you have hypercalcemia. You may non hold any specific symptoms. It may be that you merely experience unwell or a spot off colour ” . And the grade of symptoms does non ever fit up to Ca in the blood. Peoples with a somewhat high Ca degree can be really terrible symptoms, and people with a really high Ca degree may hold merely mild symptoms. Many of the symptoms are common in the advanced phases of malignant neoplastic disease, even among people who do non hold hypercalcaemia.
If hypercalcemia is non treated when symptoms become much worse and can include ( Feeling and sickness, drowsiness, Passing big sums of piss, Feeling really thirsty, desiccation, confusion, agitation, musculus spasms, shudders. Bone hurting and failing, irregular pulse, trouble in thought and speaking clearly, coma and finally decease if non treated ) Since Ca plays a function in the normal map of the encephalon and spinal cord, patients with terrible hypercalcaemia may besides ( Do fit, unable to organize musculus motions, which may impact walking, speaking and eating, alterations in personality, hallucinations Have )
Diagnosing hypercalcemia
If you have any of the symptoms of hypercalcaemia your physician will desire to analyze you and mensurate your Ca degrees with a blood trial. You may besides hold other trials and surveies to see how good your kidneys are working. If the trial shows you have high degrees of Ca in the blood, you will necessitate intervention. Until your physician can pull off your hypercalcemia they will necessitate to inquire a batch of inquiries about the narrative of your unwellness and your symptoms. It can besides be a batch to cover with if you do non experience good at the clip. You may merely desire the physician to give you something to alleviate your symptoms and leave you entirely. But it is really of import that your physician take the clip to measure all facets of your status so that you get the right diagnosing and intervention.
Preventing hypercalcemia
If you have a type of malignant neoplastic disease that is likely to do hypercalcemia, so possibly you can assist forestall or at least do certain your physician looks at the earliest. Acknowledge the symptoms of hypercalcaemia is really of import so that you can inquire your physician for aid every bit shortly as possible. Drink plentifulness of fluids and remain every bit active as possible can assist forestall hypercalcaemia.
Treating hypercalcemia
The chief purposes of intervention are to hypercalcemia ( Reduce Ca in the blood, relieving the symptoms ) , you will necessitate intervention from your specializer. You may necessitate to pass a twenty-four hours or two in the infirmary to acquire your Ca degrees down. The chief intervention for high Ca degrees are liquids, bisphosphonates and Calcitonin
liquids ( Liquids through a trickle to assist blush the excess Ca out of your system.drink plentifulness of fluids besides helps if you can manage it. )
Bisphosphonates ( Bisphosphonates ( bis-FOS-Fon-RAR ) are really effectual drugs to assist acquire your Ca degrees down. You need to hold some of these drugs via a trickle into a vena, while others come as tablets. What you need depends on how high your Ca degrees. )
Calcitonin ( Calcitonin is another medicine that you may necessitate to assist halt the debasement of bone. You have the drug by injection. You can besides hold drugs to alleviate symptoms of hypercalcaemia such as disease, irregularity, hurting or confusion. Research is ongoing into to utilize other drugs to handle hypercalcaemia.
Hypocalcemia
Why people with malignant neoplastic disease get low blood Ca
Hypocalcemia: a low blood Ca degrees. It is rare in people with malignant neoplastic disease. It may be a impermanent consequence of some malignant neoplastic disease drugs such as cisplatin and doxorubicin. Calcium Metabolism Or Calcium Homeostasis Health Essay. But it happens chiefly if you have removed the parathyroid glands in the cervix, or if they are damaged during thyroid surgery. It affects between 18 and 36 100 people ( 18 to 36 % ) . Parathyroid secretory organs can besides be damaged during other types of surgery in caput and cervix. After the caput and cervix surgery, you can ever hold a low Ca content, or they can travel back to normal after a few months. Parathyroid glands aid to keep a changeless degree of Ca in the blood. We have 4 parathyroid secretory organs in the base of our cervixs. They are little and close to the thyroid. The location of the secretory organs doing it hard for a sawbones to take the thyroid secretory organ without damaging or taking the parathyroid secretory organs during surgery. Parathyroid secretory organs make parathyroid endocrine ( PTH ) . Normally, when the degree of Ca in the blood beads, the parathyroid secretory organs make more PTH. This increases the sum of Ca in the blood by ( Bones release Ca in the blood, kidneys take more Ca back into the blood when the piss is made, the bowels absorb more Ca from nutrient )
Symptoms of low blood Ca
Many people do non hold any symptoms when their Ca is low. After surgery for thyroid malignant neoplastic disease, your sawbones will look into your blood Ca degrees before you leave hospital. You will besides hold regular cheques and these include blood trials to look into your Ca degrees. So your physician may state you that you have hypocalcemia before you have any symptoms.
Symptoms of hypocalcemia include
Painful musculus cramps and spasms, jerking of musculuss, numbness or prickling in the pess and custodies, numbness or prickling around the oral cavity. If hypocalcaemia is non found and treated, you can hold more serious symptoms, such as ( depression, dry tegument, itchiness, ictuss ( paroxysms ) – this is really rare )
Treatment for low blood Ca
If your blood Ca degrees are low, your physician will order Ca and vitamin D tablets for you. This is normally calcium in the blood at a normal degree. Eating nutrients rich in Ca may besides assist. If you start to see symptoms of hypocalcaemia after caput and cervix surgery, you must hold Ca straight into the blood stream through a trickle ( endovenous extract ) .

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1. Introduction

Calcium is the 5th of the most abundant elements in the earth crust and is also the most abundant mineral in human body. The human body contains approximately 1 kg of calcium with more than 99% deposit in the bone in the form of calcium phosphate[1]. Through interacting with numerous proteins distributed in different cellular compartments, calcium is involved in a large amount of aspects of life, such as muscle contraction, enzyme activation, cell differentiation, immune response, programmed cell death and neuronal activity [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Such broad functions are maintained by tightly controlled calcium concentration in extracellular fluid and cellular compartments. The concentrations of calcium in blood and extracellular fluid are usually maintained at 1–2 mmol/L, while the concentration of intracellular calcium at resting state is maintained at 100 nmol/L or less by calcium ATPase, channels, and exchangers located in plasma membrane and endoplasmic reticulum (ER) membrane [2], [12].  Calcium Metabolism Or Calcium Homeostasis Health Essay.During the signaling process of calcium, the concentration of intracellular calcium is increased to approximately 100 μM, which triggers calcium signaling through the activation or deactivation of an array of calcium-binding proteins. In addition, pathogens, such as bacteria and viruses, can hijack calcium signaling to benefit their own life cycles including invasion, replication and proliferation [13], [14].

Due to the regulation by calcium sensing receptor(CaSR) located in the parathyroid gland, the concentration of extracellular calcium is dedicatedly maintained by intestinal absorption, kidney reabsorption and bone resorption/formation. The miscommunication of these processes is responsible for calcium-related diseases, such as osteomalacia [15], [16]. Americans at all ages, however, do not consume enough dietary calcium compared with the recommendations by the Institute of Medicine [17]. The deficiency of calcium could cause various diseases, such as osteoporosis. In this paper, we will review the key factors controlling calcium homeostasis and further discuss the diseases associated with the dysfunctional regulation of calcium and vitamin D.

2. Molecular mechanism of extracellular calcium homeostasis

Extracellular calcium homeostasis is mainly controlled by three physiological modes, including intestinal calcium absorption, renal calcium reabsorption, and bone formation/resorption [18], which is mainly regulated by CaSR through the modulation of parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D3 secretion (Fig. 1) [19], [20], [21].

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Fig. 1. Regulation of calcium homeostasis by CaSR. The decrease of blood calcium level activates CaSR in parathyroid gland, which further promotes the secretion of PTH. Calcium Metabolism Or Calcium Homeostasis Health Essay. PHT increases blood calcium level by the direct activation of calcium reabsorption in kidney and calcium release in bone. PHT also promotes the production and secretion of 1,25-dihydroxyvitamin D3 in kidney cells. 1,25-Dihydroxyvitamin D3 regulates the intestinal calcium absorption, kidney calcium reabsorption and bone calcium release. CaSR expressed in bone, kidney and intestine cells are also involved in the regulation of calcium homeostasis.

2.1. Calcium uptake in intestine

Intestine is the major organ responsible for calcium uptake. In general, calcium from diets is absorbed by intestine through two pathways including transcellular absorption and paracellular transport of calcium (Fig. 2). In duodenum of intestine, transcellular absorption is responsible for 80% calcium uptake in low-calcium diets and less than 10% calcium uptake in high-calcium diets [22]. Certain calcium channels, intracellular calcium-binding proteins and calcium pumps are responsible for transcellular absorption of calcium. This process is initiated by transient receptor potential vanilloid type 6 (TRPV6) channel, a transmembrane calcium selective channel located in the brush border side membrane responsible for calcium entry [23], [24].Calcium Metabolism Or Calcium Homeostasis Health Essay.  After calcium enters the cell through TRPV6 channel, calcium-buffering proteins bind to calcium and transport calcium inside the cell. At last, calcium is excluded out of the cell to blood vessels through plasma membrane ATPase 1b (PMCA1b) located in the basolateral membrane [25].

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Fig. 2. Intestinal calcium absorption by transcellular absorption and paracellular transport.

TRPV6 channel belongs to the transient receptor potential (TRP) super family that contains 6 different proteins. TRPV1-4 are non-selective cation channelsactivated by protons, lipids, and the changes of temperature, pressure and osmolarity. TRPV5 and TRPV6 are calcium selective channels involved in renal calcium reabsorption and intestinal calcium absorption, respectively [18], [23], [24]. TRPV6 is located in many types of cells, including the cells from intestine, prostate cancer and breast cancer [26], [27], [28]. The activation of TRPV6 in the brush border membrane of intestine is the first step of calcium entry. This protein contains long intracellular N-terminal and C-terminal domains and 6 putative transmembrane domains. TRPV6 is also modified through N-linked glycosylation [29]. Different from TRPV1-4, TRPV5 and TRPV6 are constitutively activated [24], [30]. The functional TRPV5 and TRPV6 channels are tetramers. The expression levels of TRPV6 in intestine and many types of cancer cells are regulated by vitamin D. TRPV6 is also induced by low calcium diets or at the time of weaning [31], [32]. Transgenic mice with TRPV6 overexpression can result in hypercalcemia and soft tissue calcification, which further supports the role of TRPV6 in calcium absorption [31], [33]. Additionally, TRPV6 is regulated by multiple intracellular proteins including calmodulin, S100A10/Annexin 2, Nipsnap1 and Rab11a [34], [35], [36], [37]. TRPV6 also contains a few putative phosphorylation sites, suggesting that TRPV6 is modulated by kinases [22].

The second phase of transcellular absorption for calcium is mediated by a calcium-buffering protein, calbindin D9k as an intracellular calcium-binding protein. This protein has one classical EF-hand and one pseudo EF hand. Both EF-hands cooperatively bind calcium with high affinity [38], [39]. Unlike parvalbumin [40], [41], calbindin D9k has relatively low affinity to Mg²⁺. The expression level of calbindin D9k in intestine can be regulated by 1,25-dihydroxyvitamin D3, low dietary calcium conditions or at the time of weaning [31], [32], [42]. Calcium Metabolism Or Calcium Homeostasis Health Essay.

Although the roles of TRPV6, calbindin D9k and PMCA1 in transcellular calcium absorption are well studied, the studies with gene knockout mice suggest that TRPV6 channel and calbindin D9k are not essential for the intestinal calcium uptake and the functions of TRPV6 and calbindin D9k in transcellular calcium absorption may be compensated by other proteins [43], [44].

The third step of transcellular calcium absorption is mediated by PMCA1b. As a common mechanism of PMCA, PMCA1b transports intracellular calcium to blood in an energy-dependent meaner. Animals adapted to diets with low calcium and low phosphorus or induced by vitamin D can increase the expression of PMCA1b in the basolateral membrane of intestinal cells [45], [46]. Besides, sodium–calcium exchangersincluding NCX1, are also involved in calcium extrusion in the basal lateral membrane [22].

Different from transcellular absorption of calcium, paracellular transport of calcium is a non-saturable, energy-independent pathway. Paracellular transport of calcium can be observed throughout the intestine and is the major pathway for calcium uptake, especially under the condition with high-calcium diets. Compared with transcellular calcium absorption, the molecular mechanism of paracellular calcium transport is less well studied. However, it is clear that tight junction plays a critical role in the regulation of this event. The permeability of tight junction is regulated by many proteins including claudin 2 and 12 [22], [31]. In addition, 1,25-dihydroxyvitamin D3 regulates paracellular calcium transport by suppressing the expression of claudin 3, aquaporin 8, cadherin 17, and RhoA, thus improving the permeability of tight junction [47], [48].

2.2. Calcium reabsorption in kidney

Kidney is another essential organ for calcium sensing and reabsorption. Calcium is absorbed in nephronwith the highest absorption in proximal tubules [18]. The renal calcium reabsorption comprises of two pathways including paracellular pathway and transepithelial pathway. Similar as transcellular calcium absorption in intestine, transepithelial calcium reabsorption in kidney also contains three major steps. First, calcium is transported to the intracellular space through calcium channels located in the epical membrane. TRPV5 is the major calcium channel located in the epical plasma membrane responsible for calcium transportation. TRPV5 is a calcium-selective channel with 75% amino acid identity to TRPV6 [18], [49]. The N-terminal of TRPV5 contains six ankyrin repeats involved in the tetramer formation and protein–protein interaction. The C-terminal of TRPV5 contains a phosphorylation site of protein kinase C. The kidney calcium reabsorption is impaired in TRPV5 knockout mice, suggesting the critical role of TRPV5 in this process [18], [50]. TRPV5 is regulated by many biomolecules, and can be activated by kallikrein or bradykinin receptor through PLC/DAG/PKC pathway [51]. Similar to TRPV6, TRPV5 is regulated by annexin-2, Rab11a, calmodulin and other proteins [18], [24]. Second, the intracellular calcium binds to calcium-buffering proteins, such as calbindin D28k and calbindin D9k, and passively diffused to the basolateral membrane through calcium gradient. Calbindin D28k contains three pairs of EF-hand motifs with 6 calcium-binding sites. This protein dynamically controls calcium reabsorption through the interaction with TRPV5 at low intracellular calcium concentration [52]. Renal calcium reabsorption is disrupted in calbindin D28k knockout mice with high calcium diets [18], [53], while other group shows that the effect of calbindin D28k on calcium transport is compensated by other proteins including calbindin D9k [18], [54]. At last, calcium is transported to blood by PMCA1b and/or NCX1 located in the basolateral membrane.

Calcium reabsorption in kidney is modulated by PTH, 1,25-dihydroxyvitamin D3 and estrogen. PTH reduces the expression levels of TRPV5, calbindin D28k, PMCA1b and NCX1 in kidney cells through PTH receptor (PTHR)-mediated signaling pathway. PTH also stimulates the production of 1,25-dihydroxyvitamin D3 in proximal tubules. 1,25-Dihydroxyvitamin D3, produced from kidney and other organs, down-regulates the expression of TRPV5, NCX1 and calbindin D28k in kidney cells. The expression level of PMCA1b in these cells, however, is not significantly affected by 1,25-dihydroxyvitamin D3. Additionally, animal experiments also suggest that certain estrogen can increase the expression of renal reabsorption-related proteins, such as TRPV5, PMCA1b, calbindin D28k and NCX1 [18], [55].

2.3. Bone calcium regulation

Besides intestinal absorption and renal reabsorption of calcium, bone resorption is an important mechanism to modulate calcium level in blood. Bone is constantly remodeled by osteoblasts and osteoclast. Osteoblasts facilitate bone formation, while osteoclasts break bone tissue and release calcium. The development and activation of osteoclasts are mediated by receptor activator of NF-κB (RANK) ligand (RANKL). The expression of RANKL is promoted by vitamin D3, PTH, PTHrP, TNF-α, IL-1, IL-6, IL-11 and IL-17 and inhibited by TGF-β [57], [58], [59], [60], [61], [62]. On the other hand, the activity of RANKL is also inhibited by osteoprotegerin (OPG), a secreted protein functioning as a decoy receptor for RANKL.Calcium Metabolism Or Calcium Homeostasis Health Essay.  OPG disrupts the interaction between RANK and RANKL by competitively binding to RANKL, and functions as an inhibitor for the development and activation of osteoclasts. The expression level of OPG in human bone marrow cells is inhibited by 1,25-dihydroxyvitamin D3 and PTH [63], [64], [65]. Thus, 1,25-dihydroxyvitamin D3 and PTH modulate calcium resorption in bone by increasing RNAKL expression and decreasing OPG expression.

2.4. Calcium homeostasis by CaSR regulation

Calcium level in blood is mainly maintained by CaSR located in the parathyroid gland. CaSR belongs to family C of G-protein coupled receptor. Other members in this family include metabotropic glutamate receptor, GABA_B receptor and taste receptor[66], [67], [68], [69]. CaSR has seven transmembrane domains. The length of the extracellular and intracellular domain of CaSR varies in different cell types due to alternative splicing. The N-terminal of extracellular domain of CaSR contains more than 500 residues. It interacts with multiple ligands, indicating that this protein has multiple functions in sensing micro-environmental changes. CaSR is usually expressed as homodimer or heterodimers in the plasma membrane. A cysteine rich region located in the extracellular domain of CaSR is critical for the dimerization of CaSR [70], [71].

The C-terminal of intracellular domain of CaSR interacts with many cell signaling proteins [72]. Protein kinase C regulates CaSR functions by the phosphorylation of several serine residues in the intracellular domain. An ubiquitin ligase, dorfin, dynamically interacts with intracellular domain of CaSR, and regulates trafficking and degradation of CaSR [73]. Like other G-protein coupled receptors, CaSR is phosphorylated by G protein receptor kinases (GRKs) in the second or third loop [72]. The β-arrestinbinds to the phosphorylated loop and blocks the interaction between CaSR and G-protein. The β-arrestin binding also facilitates the receptor internalization and activates ERKs in a G protein-independent manner [74]. Filamin is a scaffold proteinthat interacts with CaSR and modulates CaSR signaling [75]. CaSR also interacts with caveolin-1, a 22 kDa transmembrane protein extensively expressed in caveolea [76], and regulates the expression and activation of inducible nitric oxide synthase (iNOS) [77]. Caveolin-1 also can be involved in trafficking of cholesterol and sphingolipids, and serve as a scaffold protein to modulate signaling transduction. However, the functions of intestinal chloride ion channel and exchangers regulated by CaSR are not clear yet, although CaSR is able to modulate Ca²⁺ and IP3 dependent Cl⁻ current in CaSR-overexpressed oocytes[78].

One of the major functions of CaSR is regulating systemic Ca²⁺ homeostasis [79], [80]. Ca²⁺ is the primary ligand of CaSR. At least four calcium-binding sites are reported in the extracellular domain of CaSR. CaSR cooperatively binds to Ca²⁺ when extracellular concentration of Ca²⁺ increases [81], [82]. CaSR is also able to sense Mg²⁺, amino acids, pH, antibiotics and peptides, and subsequently activates downstream G_i (G inhibitory) and G_q as well as G_12/13 pathways [80]. The activation of CaSR can inhibit cAMP production, activate ERK pathway through G_i pathway, activate PLC-IP3 cascades, and release Ca²⁺ from ER via G_qpathway. It also can activate Rho and phospholipids D by G_12/13 pathway [72]. In healthy individuals, a slight change of calcium concentration in the extracellular fluid can trigger the downstream signaling of CaSR in the parathyroid gland, which can further induce the change of PTH secretion and subsequently influence the cells in intestine, kidney and bone to adjust the concentration of extracellular calcium [70], [83]. Calcium Metabolism Or Calcium Homeostasis Health Essay.

CaSR regulates extracellular calcium levels in several aspects (Fig. 1). First, CaSR regulates the secretion of PTH that has direct effects on calcium reabsorption in kidney and bone remodeling. Second, the increase of PTH stimulates the production and secretion of 1,25-dihydroxyvitamin D3 in proximal tubules as the key molecule for the regulation of the intestinal calcium absorption, kidney calcium reabsorption and bone calcium release [83]. Third, the activation of CaSR, in some cases, inhibits the activity of osteoclasts, which further suppresses bone calcium release [84]. Forth, CaSR further modulates extracellular calcium level by regulating calcitonin selection in thyroidal C-cells [85], [86]. Moreover, CaSR is highly expressed in the digestive system including pancreas, stomach, small intestine and large intestine. In small intestine, CaSR modulates motility and development of intestine, NaCl and H₂O transport, Ca²⁺/Mg²⁺ absorption and nutrient absorption [87]. Furthermore, CaSR expressed in renal tubules also can directly regulate the filtering and reabsorption of metal ions, including calcium [70].

3. Calcium diets, supplements, vitamin D and diseases

Food is an important source for calcium uptake. The common calcium-rich foods include milk, yogurt, cheese, shrimp, soybean, soy milk, tofu, broccoli, orange, kale and others. The major forms of calcium supplements are calcium carbonate and calcium citrate. Americans at all ages, however, do not take enough dietary calcium compared with the recommendations by the Institute of Medicine [17]. Sufficient calcium intake is important for human health and calcium deficiency could lead to diseases, such as osteoporosis and rickets [88], [89].

Bone is a living and constantly remodeling tissue [90]. The old or damaged bone is resorbed by osteoclastsand the new bone is constructed by osteoblasts [56]. Bone is primarily composed of organic components and inorganic components. The organic components are consisted mainly of type I collagen responsible for bone flexibility. The inorganic components comprised of hydroxyapatite, insoluble salts containing calcium and phosphorus provide bone strength against compression [90]. The concentration of calcium in serum is usually kept in a very limited range so as to prevent the disorder of some physiological functions, such as muscle contraction [91]. Bone is a mineral reservoir for calcium and phosphorus. Over 99% of total calcium in human body is stored in bone and teeth. Calcium plays important roles in the formation process of new bone and maintenance of existing bone by collaborating with other factors such as phosphorus, vitamin D and calcium-binding proteins [92].

Dietary calcium intake is critical for the calcium homeostasis of bone. Supplementary diets containing calcium with average recommended dietary allowancefor children increase bone mineral density (BMD) and reduce the risk of fracture [93]. As reviewed in the previous section, calcium homeostasis is well maintained in the cells from intestine, kidney and bone. When serum calcium level is low, CaSR promotes the secretion of PTH and indirectly increases 1,25-dihydroxyvitamin D3 level. When dietary calcium intake from intestine is low, blood calcium level is maintained by kidney reabsorption and bone calcium release at the expense of bone strength [94].Calcium Metabolism Or Calcium Homeostasis Health Essay.  On the other hand, lack of vitamin D could cause serious health problems. Low vitamin D level limits the synthesis of 1,25-dihydroxyvitamin D3, which further reduces blood calcium level through the inhibition of intestinal calcium absorption and renal calcium absorption. The PTH level, however, increases in response to the reduced blood calcium level. The increase of PTH promotes bone remodeling, while low calcium inhibits bone mineralization, correspondingly leading to the increased osteoid [94].

Some studies have demonstrated that patients with specific diseases or disease treatments may have skeletal abnormalities. For example, valproate, a chronic antiepileptic therapy, may cause low bone mass in pediatric patients and sufficient intake of calcium can offset this harmful effect [95]. BMD is significantly lower in patients with Parkinson’s diseasethan the healthy people and the lower BMD is correlated with severe progression of the disease [96]. The loss of BMD is the early sign of osteopenia that can turn into osteoporosis. Osteoporosis can lead to fracture and other severe bone diseases. Current studies reveal that adequate intake of calcium can decrease the risk of osteoporosis, fracture and diabetesin some cases [92].

The role of calcium in cancer has been explored for almost 100 years [97]. The relationship between calcium and cancer, however, is still controversial. A previous randomized trial has demonstrated that the supplementation of calcium and vitamin D for seven years has no effects on colorectal cancer [98]. High calcium intake, however, seems to reduce the risk of breast cancer and the increase the risk of prostate cancer [99]. Breast cancer is the most common cancer in women in the United States and China [100]. Early diagnosis, prognosis and treatment of cancers through biomarkers, such as HER-2 and gastrin-releasing peptide receptor (GRPR), are actively studied in animal models [101], [102], [103], [104], [105], [106]. On the other hand, cancer prevention through diet interventions is a hot topic with the aim of reducing and preventing cancer occurrence. High calcium intake seems to reduce the risk of some cancers, such as breast cancer [99]. Vitamin D and calcium shows anti-breast cancer effects through regulating signaling pathwaysassociated with cell proliferation, invasion and apoptosis. Epidemiological studies show that the intake of dietary and supplementary calcium and vitamin D reduces the risk of breast cancer. Additionally, the levels of serum calcium and vitamin D metabolites are inversely correlated with breast cancer [107]. The mutations in vitamin D receptor and calcium sensing receptor are also identified in breast cancer tissue, suggesting the involvement of calcium and vitamin D signaling in breast cancer [107], [108], [109]. TRPV6 can exhibit the up-regulation by 2–15 folds in breast cancer tissue when compared with that in normal breast tissue. The expression level of TRPV6 is reduced in breast cancer cell lines in the presence of tamoxifen, an antagonist of estrogen receptor [110], and can be up-regulated by 1,25-vitamin D. Calcium Metabolism Or Calcium Homeostasis Health Essay. The overexpression of TRPV6 is also observed in the highly invasive area of breast cancer [111]. Therefore, further studies on the relationship between dietary vitamin D/calcium and TRPV6 in breast cancer are highly desired.

Additionally, dietary calcium involves in cardiovascular diseases. High calcium intake could induce fatty acids and bile to bind to calcium, which further inhibits intestinal calcium absorption and therefore reduces cholesterol level in blood [112], [113], [114]. Blood calcium also regulates blood pressure by modulating renin-angiotensin system [113], [114], [115].

Whether calcium supplements can be beneficial or harmful to the health of people is still controversial. Although the effects of calcium supplements or casual calcium uptake on health outcomes have been systematically reviewed [99], the risks of calcium supplements for cardiovascular diseases have not been completely understood [116]. High calcium intake can slightly improve BMD in children and pregnant woman. There is no consistent conclusion between calcium intake and cardiovascular diseases, except blood pressure. Similarly, although some studies show that people with high calcium intake has lower chance of overweight and obesity [117], the relationship between calcium and obesity is still controversial. Calcium supplementation in diets can contribute to the reduced rate of bone loss and fracture incidence in elders; however, it can also increase the risks of acute gastrointestinal events, kidney stone, and cardiovascular diseases such as myocardial infarctionand stroke [118], [119]. Based on the meta-analysis, only 10% fracture incidence is reduced due to the calcium supplementation, but the incidences of myocardial infarction and stroke are increased up to 27%–31% and 12%–20%, respectively [119]. Moreover, high calcium intake for men also has the potential for the risk of advanced and fatal prostate cancer [17], [120], [121]. Calcium Metabolism Or Calcium Homeostasis Health Essay.

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4. Conclusion

Calcium is the most abundant mineral in human body with 99% deposit in bone. The intestinal absorption, kidney reabsorption and bone resorption are three major events for calcium homeostasis regulated by CaSR through a series of complicated mechanisms. Any miscommunication of these processes can lead to diseases associated with dysfunctional regulation of calcium. In addition, calcium in diets and supplements along with vitamin D play critical roles in calcium homeostasis. Low calcium intake or low vitamin D level can also result in bone diseases. High calcium intake can reduce the risk of breast cancer and contribute to the reduced rate of bone loss and fracture incidence in elders. On the other hand, although high calcium intake can reduce the risk of many diseases, it also can increase the risks of acute gastrointestinal events, kidney stone, and cardiovascular diseases such as myocardial infarction and stroke. Therefore, the consumption and supplementation of calcium should abide by the health status of individuals.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This work is financially supported by the National Natural Science Foundation of China (No. 31571228), Chutian Scholar Program from Education Department of Hubei Province and Innovative Start-up Foundation from Wuhan Sports University to NC. Calcium Metabolism Or Calcium Homeostasis Health Essay.