Calcium metabolism

Calcium and Phosphate

Calcium is present in the human body in high amounts in the form of calcium phosphate, forming hydroxyapatite crystals. These crystals are found:

99% in bone tissue and teeth and 1 kg is found in adult bones. while the remaining 1% constitutes the extracellular pool exchangeable in plasma in amounts of 10 mg%; of this half, 5mg%, is bound to proteins, mainly albumin, the other half, 5mg%, is present in the form of ionized calcium. The other half, 5 mg%, is present in the form of ionized calcium. 10/15% is weakly bound to anions: phosphates, sulfates and lactate; the remaining part, 4.5 mg% is free calcium, useful for electrical conduction, signal translation, etc... 

Intracellular ionized calcium is very low, about 100 nM. The presence of high concentrations of inorganic phosphate in the cytosol requires that the calcium concentration be low, because if inorganic phosphate binds to calcium it would lead to the formation of calcium phosphate [Ca₃(PO₄)₂], a relatively insoluble product. Calcium ions are therefore actively pumped out of the cell by an ATPase that resides on the plasma membrane; another ATPase calcium pump is located in the RE and serves to accumulate calcium within the cisternae of the endoplasmic reticulum. 

In the sarcoplasmic reticulum of myocytes is located the ATPase calcium pump called SERCA.

The daily requirement of calcium is 300 mg per day, but since only 30% is absorbed by the intestine (especially duodenum), the recommended doses are only 1000/1200 mg per day. 

Free calcium, which is the physiologically active form, is fine-tuned and, to detach it from proteins, protons must be bound in its place A decrease in PH acidosis causes calcium to detach, while an increase in PH alkalosis decreases free calcium (hypocalcemia). Fifty percent of total calcium in the blood is not bound to proteins and is ultrafiltratable; ultrafiltratable calcium includes calcium that is complexed into anions, such as phosphate, and free ionized calcium. 

Each day, 200 mg of calcium is absorbed from the intestine and subsequently passes into the bloodstream, 80%.Approximately 800 mg per day of the daily calcium intake, is excreted in the feces. With the exception of the phosphate portion that is excreted in the feces in combination with unabsorbed calcium, almost all of the dietary phosphate is absorbed into the bloodstream from the intestine and subsequently excreted in the urine. The intestine (ABSORPTION), skeleton (DEPOSIT), and kidney (EXCRETION) thus play an essential role in ensuring calcium homeostasis. About 1 kg of calcium is deposited in the bones, of which about 0.5 g is mobilized and redeposited daily. There is an active exchange between the two compartments, every day 500 mg are exchanged between blood and bone for its continuous turnover. In addition to intestine and bone, kidney is also important for calcium metabolism, kidneys filter about 10 g per day, reabsorb almost all and eliminate 200 mg per day in urine, in balance with intestinal absorption. Roughly the same amount of calcium is lost in the kidney as was taken in. 

Calcium, besides being useful for bone mineralization, is essential for the action of many enzymes, for blood coagulation, for muscle contraction, for neuro-muscular excitation, for exocrine and endocrine secretion, for signal transduction and is an important second messenger. Calcium level is strongly affected by phosphate level; inorganic phosphate is found 80% in mineralized bone, and 20% in intra- and extra-cellular fluids. If a hypercalcemia is associated with a hyperphosphatemia, calcium may also crystallize and precipitate in soft tissues other than bone. The reason calcium is deposited primarily in bone is because proteins are present that allow it to do so. Plasma calcium is 10 mg per 100 mL, of which about half travels bound to proteins.

If you vary the normal level of calcium you have very serious effects: a hypercalcemia reduces the transmission of neurons, also causes constipation and stones; a hypocalcemia causes a hyper excitability of neurons, muscle cramps, tetany, convulsions; the same type of hyperactivity can be seen in the larynx and bronchi, causing spasms, even the sensory fibers can be hyper excited, causing paresthesias. 

There are two particular ways that help to detect a hypocalcemia: the Trousseau sign, which is induced by putting a sphygmomanometer on the arm and pumping air until the arterial blood flow is reduced. In conditions of hypocalcemia there is the so-called carpal spasm, or carpo-podal spasm or, if performed on the face, Chvostek's sign, in which the upper part of the masseter is struck, in front of the ear, and in conditions of hypocalcemia there is a contracture of the hemiface on the side where the stimulation occurred.

In ossification there are collagenE proteins and non-collagenE proteins with different functions. the latter can be osteocalcin, osteonectin, osteopontin, proteoglycans etc..., and while some promote the formation of calcium microcrystals, others promote the division of bone cells. They are therefore important proteins in controlling the degree of mineralization.

Hydroxyapatite crystals consist of calcium, phosphate and hydroxyl groups. Under special conditions these three elements can be replaced by others, for example after a radioactive fall out calcium can be replaced by strontium 90 which is extremely toxic.

Osteoblasts produce collagen and after depositing need calcium phosphate deposition; this is accomplished by the deposition of calcium vesicles and the presence of alkaline phosphatases. Alkaline phosphatases hydrolyze phosphate monoester, detached from phosphorylated proteins, into phosphate ions. 

In the development of osteoclasts, multinucleated cells derived from the macrophage monocyte lineage, communication with osteoblasts is important because osteoblasts release macrophage colony stimulating factor (MCSF), which stimulates the maturation of macrophages into osteoclasts. Osteoblasts also release RANK-L, which remains on the osteoblast membrane and interacts with a RANK molecule on macrophages. Osteoprotegerin binds to RANK-L, which prevents its binding to RANK on macrophages and prevents their differentiation.

Activated osteoclasts digest bone by releasing protons, chloride ions, hydrolases, and metalloproteases (MMPs). Through the combined action of these elements, both the organic and inorganic parts are digested. The activity of osteoblasts and osteoclasts is highly balanced and allows the bone to adapt to the different stresses to which it is subjected. 

Remodeling is the ordered sequence of bone resorption and formation; 10% of each bone is renewed each year. Phosphate is present in bone at 85% and in intra- and extra-cellular fluids at 15%. Calcium and phosphate ion levels must be highly balanced: [Ca] x [P] = solubility product.

PARATORMONE (PTH)

Parathormone is produced when the blood calcium level is low; it is secreted by the parathyroid cells, which are in contact with the thyroid tissue. It is a small protein of 84 amino acids synthesized as preproPTH and accumulated in granules, so-called secretion vesicles.

In parathyroid cells if plasma calcium is high this results, (via a seven-step, G-protein bound calcium sensor receptor) in the activation of phospholipase C and the formation of inositol 3P which results in the release of calcium from the endoplasmic reticulum and an increase in intracellular calcium. Intracellular calcium inhibits, in this case, the release of parathormone from secretory vesicles; this is one of the few cases in which calcium inhibits anything. If, on the other hand, extracellular calcium is low, it increases parathormone synthesis and secretion, via the PKA and cAMP pathway. Vitamin D, or calcitriol, inhibits parathormone release, this is because PTH stimulates vitamin D production. Being a protein, parathormone has a very low stay in the circulation, acting on bone, kidney and indirectly on the intestine. The kidney is the central organ in calcium regulation, PTH determines the fine tuning of this renal function. Sixty-five percent of filtered calcium is reabsorbed in the proximal tubule in a constitutive, unregulated manner, together with sodium and H2O; approximately 20% of filtered calcium is reabsorbed in the ascending tract of Henle's loop, and approximately 15% of filtered calcium is reabsorbed in the distal convoluted tubule, under control of PTH. The excreted portion is quantitatively minimal, approximately 0.2 g/day out of 10 g/day of ultrafiltrate, i.e., 2%. Therefore, at the level of the kidney, parathormone stimulates an increased reabsorption of calcium in the distal tubule, but there is also, above all, an increased release of phosphate in the proximal tubule.

The entry of calcium is due to the transport of calcium channels on the membrane; calcium cannot leave the cell on the luminal side because on the basal side are synthesized and exposed transporters that clearly transport calcium in the blood, instead the parathormone in the proximal tubule binds to the receptor, activates PKA and allows the withdrawal of phosphate transporters from the membrane (they are sodium-phosphate cotransporters) thus preventing phosphate from being reabsorbed. In addition, KREB is activated, which stimulates the synthesis of 1-alpha-hydroxylase, which catalyzes vitamin D synthesis. Finally on bone, osteoclasts are not directly stimulated, as they do not have a receptor, but instead osteoblasts are stimulated, which increase the levels of MCSF, RANK-L and lower the levels of OSTEOPROTEGERIN, which serves to increase the number of osteoclasts that will digest more bone. Thus, PTH stimulates the resorption of bone by osteoclasts and the subsequent release of calcium and phosphate into the interstitial fluid. The level of calcium and phosphate thus increases but there is no precipitation because in the kidney calcium is absorbed at the proximal convoluted tubule in a constitutive manner and phosphate is excreted. 

Finally, PTH stimulates the synthesis of prostglandins in osteoblasts that have a function in bone resorption. With regard to the intestine, parathormone also increases renal 1-alpha-hydroxylase activity, with increased production of 1,25-hydroxy-vitamin D and increased absorption of calcium and inorganic phosphate by the small intestine. Thus, PTH also activates vitamin D, which in turn stimulates calcium absorption.

CALCITONIN (CT)

Calcitonin, also called thyrocalcitonin because it is produced by the C cells of the thyroid, which are not part of the follicle wall and pour calcitonin into the capillaries, is another regulatory hormone of calcium metabolism.

Calcitonin is also a peptide and is synthesized in the form of prepro-calcitonin, it has opposite effects to those of parathormone and when calcium exceeds a certain level besides inhibiting the secretion of parathormone, it increases the secretion of calcitonin. The receptor increases the levels of cyclic AMP and PLC. Calcitonin has a primary role on osteoclasts that have a specific receptor, in the presence of calcitonin the activity of osteoclasts is inhibited. 

In the kidney it determines the lowering of calcium and phosphate reabsorption. However it is believed that parathormone is sufficient to determine calcium levels, while calcitonin seems to have a much more marginal role.