Parathyroid hormone, Calitonin, Calcium and Phosphate metabolism, Vit. D, Bone, and Teeth

Created by cmagliulo 

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Hypercalcemia and hypocalcemia effects on neurons

Hypercalcemia - progressive depression

Hypocalcemia - causes nervous system to become excited -->tetany

which form of calcium is most important for functions in the body

-IONIZED
*calcium ion concentration is only one-half the total plasma ion concentration

Two forms of inorganic phosphate in the plasma

-HPO4
-H2PO4- more of this present relative to HPO4 when the env is more acidic

**changing phosphorous levels does not have much of an effect

Hypocalcemia

-nervous system becomes progressively more excitable because this causes increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials

*At plasma calcium ion concentrations about 50% below normal, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously -->tetanic muscle contraction

from 9.4 mg/dL (normal [] of calcium) ---> 6 mg/dL

Hypercalcemia

-nervous system becomes depressed and reflex activities of the CNS are sluggish
-it also decreases the QT interval of the heart and causes lack of appetite and constipation, probably because of depressed contractility of the muscle walls of the GI tract
-when blood levels rise above 12 mg/dL
-when they rise above 17 mg/dL calcium phosphate crystals begin to appear --> PARATHYROID POISONING

About ___% of the ingested calcium is excreted in the urine. About ___ % of the plasma calcium is bound to plasma proteins and is not filtered by the glomerular capillaries. ___% is combined with anions such as phosphate and ___% is ionized and filtered into the renal tubules

-10%
-41%
-9%
-50%

About ____ % of the ingested calcium is usually absorbed

-35%
-350 mg/day
-250 mg/day are sloughed off or secreted via GI juices

-900 mg/day is lost in feces

Approximately 90% of the calcium in the glomerular filtrate is reabsorbed in the ____, ____ and ____.

Then in the ___ and _____, reabsorption of the remaining 10% is selective, depending on the calcium ion concentration in the blood

-proximal tubules, loops of Henle, and early distal tubules

-late distal tubules and early collecting ducts

-PTH is most important controlling factor in this 10%

Overflow mechanism of renal plasma phosphate control

-when phosphate concentration in the plasma is below the critical value of ~1 mmol/L, ALL the phosphate in the glomerular filtrate is reabsorbed and no phosphate is lost in the urine
-but above this critical concentration, the rate of phosphate loss is directly proportional to the additional increase

**PTH can greatly increase phosphate excretion by the kidneys

Bone composition

-30% matrix = 90-95% collagen fibers (give bone its tensile strength) and the remainder is a homogenous gelatinous medium called ground substance (composed of EC fluid and proteoglycans (especially chondroitin sulfate and hyaluronic acid)

-70% bone salts = composed of calcium and phosphate --> crystalline salt known as hydroxyapatite: Ca10(PO4)6(OH)s
-magnesium, sodium, potassium, and carbonate are also present in bone salts
*salts have great COMPRESSIONAL STRENGTH

why does hydroxyapatite not precipitate in extracellular fluid despite supersaturation of calcium and phosphate ions?

-Inhibitors of precipitation = pyrophosphate

Mechanism of Bone Calcification

1) secretion of collagen molecules (collagen monomers) and ground substance by OSTEOBLASTS

2) collagen monomers polymerize rapidly to form collagen FIBERS; the resultant tissue becomes OSTEOID, a cartilage-like material differing from cartilage in that calcium salts readily precipitate in it

3) As the OSTEOID is formed, some of the osteoblasts become entrapped in the osteoid and become quiescent. At this stage they are called OSTEOCYTES

4) w/in a few days calcium salts begin to precipitate on the surfaces of the collagen fibers in intervals. the salts are initially amorphous but become hydroxyapatite crystals over a period of weeks and months

exchangeable form of calcium

-normally amounts to about .4-1% of total bone calcium
-this calcium is deposited in bones in a form of readily mobilizable salt such as CaHPO4 and other amorphous calcium salts

Mechanism of osteoclast bone absorption

-osteoclasts send out villus-like projections toward the bone, forming a ruffled border adjacent to the bone. The villi secrete 2 types of substances:
1) proteolytic enzymes - from lysosomes of the osteoclasts. digest or dissolve the organic matrix
2) several acids (citric and lactic) from the mitochondria and secretory vesicles. cause dissolution of the bone salts

PTH

-binds to receptors on adjacent osteoblasts, causing them to release cytokines, including osteoprotegerin ligand (OPGL), which is also called RANK ligand. OPGL activates receptors on preosteoclast cells, causing them to differentiate into mature multinucleated osteoclasts. The osteoclasts then develop a RUFFLED BORDER and release enzymes and acids that promote bone resorption

OPG

-released by osteoblasts
-binds OPGL and inhibits its function (prevents osteoclast function)
-estrogen stimulates OPG production

Vitamin D3 (cholecalciferol)

-is formed in the skin as a result of irradiation of 7-dehydrocholesterol, a substance normally in the skin, by UV rays from the sun
-same function as dietary Vit. D

Cholecalciferol is converted to ____ in the liver. This is then converted to ____ in the proximal tubules of the kidney

-25-Hydroxycholecalciferol in the liver (with a feedback inhibition mech that prevents excessive action of vit. D when intake of vit. D3 is altered over a wide range. This also conserves the vit. D in the liver for future use.

-1,25-Dihydroxycholecalciferol (most important/potent form of vit. D)
**this is why absence of kidneys --> loss of vit. D function
$$This conversion requires PTH

2 ways calcium ion concentration controls the formation of 1,25-Dihydroxycholecalciferol

1) increased plasma Calcium -->suppressed PTH secretion and 25-hydroxycholecalciferol is converted to another compound 24,25-dihydroxycholecalciferol that has almost no Vit. D effect

2) the calcium ion itself has a slight effect in preventing the conversion

Vitamin D receptors

-present in most cells
-located mainly in the nuclei of target cells
-has hormone-binding (1,25-Dihydroxycholecalciferol) and DNA binding domains
**The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and this complex binds to DNA and activates transcription in most instances
-in some cases vitamin D suppresses transcritpion

hormone action of 1,25 Dihydroxycholecalciferol

-increases, over a period of two days, formation of CALBINDIN, a calcium binding protein, in the intestinal epithelial cells (functions in the brush border to transport calcium into the cell cytoplasm)
-then the calcium moves through the basolateral membrane of the cell by facilitated diffusion
-also forms a calcium-stimulated ATPase in the brush border of the epithelial cells AND an alkaline phosphatase in the epithelial cells

*promotes phosphate absorption as well
*decreases renal calcium and phosphate excretion

In the absence of vit. D, the effect of PTH in causing bone absorption is greatly ____

-reduced or even prevented
*vitamin D in smaller quantities promotes bone calcification

Excess activity of the Parathyroid gland

-causes rapid absorption of calcium salts from the bones, with resultant hypercalcemia in the extracellular fluid
-opposite is true

The administration of extreme quantities of vitamin D causes ____

-absorption of bone

The ___ cells of the parathyroid glands are believed to secrete most of, if not all of the PTH

-chief cells

**usually 4 parathyroid glands

Chemistry of PTH

1) first synthesized on the ribosomes in the form of a preprohormone, a polypeptide of 110 amino acids

2) cleaved to prohormone w/ 90 aa's

3) then to 84 aa's (the hormone itself)

**smaller compounds with as few as 34 aa's have also been isolated and may account for a large share of the activity considering that the kidneys rapidly remove the 84 aa hormone w/in minutes

The rise in calcium concentration is caused by (2)

1) an effect of PTH to increase calcium and phosphate absorption from the bone

2) a rapid effect of PTH to decrease the excretion of calcium by the kidneys

**The decline in phosphate concentration is caused by a strong effect of PTH to increase renal phosphate excretion that is strong enough to override increased phosphate absorption from bone

Rapid phase of calcium and phosphate absorption from bone (osteolysis):

PTH causes removal of bone salts from two areas in the bone (2)

1) from the bone matrix in the vicinity of the osteocytes lying within the bone itself

2) in the vicinity of the osteoblasts along the bone surface

**osteocytic membrane system = long, filmy processes extend from osteocyte to osteocyte throughout the bone structure and they also connect with surface osteocytes and osteoblasts

*B/w the the osteocytic membrane and the bone is a small amount of BONE FLUID. the osteocytic membrane pumps calcium ions from the bone fluid into the extracellular fluid, creating a calcium ion concentration in the bone fluid only 1/3 that in the ECF. When the osteocytic pump becomes excessively activated, the bone fluid calcium concentration falls even lower, and calcium phosphate salts are then absorbed from the bone

$$ the cell membranes of both the osteoblasts and osteoclasts have receptor proteins for binding PTH --> PTH can activate the calcium pump strongly (increasing calcium permeability of the bone fluid side of the osteocytic membrane --> allowing Ca to diffuse into the membrane cells --> and the through a calcium pump into the ECF

Slow Phase of bone absorption and calcium phosphatase release -- activation of the Osteoclasts

-secondary signals from osteoblasts and osteocytes activated by PTH
-major secondary signal is OSTEOPROTEGERIN LIGAND, which activates receptors on preosteoclast cells and transforms them into mature osteoclasts
-over a period of weeks or months

** there is an immediate activation of already formed osteoclasts AND formation of NEW osteoclasts

The increased calcium absorption due to PTH happens in the ____

-distal tubules, the collecting tubules, the early collecting ducts (10%)

PTH hormone increases intestinal absorption of calcium and phosphate from the intestines by ____

**increasing the formation in the kidneys of 1,25-dihydroxycholecalciferol

-use the cAMP second messenger for this function as well as for the secretion of enzymes by osteoclasts

Changes in extracellular fluid calcium ion concentration are detected by a ____

-calcium-sensing receptor (CaSR) in the parathyroid cell membranes - it is a G-protein coupled receptor that activates phospholipase C when stimulated by Calcium ions --> etc. --> release of intracellular stores of Calcium -->decreases PTH secretion by the cell
-immediately sense even the smallest decrease in blood calcium and secrete PTH in response w/in minutes (may also hypertrophy: especially during lactation, pregnancy, rickets). Opposite happens when there is no Calcium ions.

Calcitonin, a peptide hormone secreted by the ____, tends to ____ plasma calcium concentration

-thyroid gland
-decrease
*in general has opposite effects to those of PTH

Synthesis and secretion of calcitonin occur in the ____ cells

-parafollicular cells, or C cells, lying in the interstitial fluid b/w the follicles of the thyroid gland

Calcitonin

-increased plasma calcium concentration stimulates calcitonin secretion
-prolonged effect of decreasing the formation of new osteoclasts
-immediate effect of decreasing the absorptive activities of osteoclasts
**only a transient effect because over time the decreased osteoclasts lead to decreased numbers of osteoblasts (activated/formed in weakened bone state) It is also WEAK and overrided by PTH effect

Exceptions: in children (fast bone remodeling), in Paget disease = in which osteoclastic activity is greatly accelerated and calcitonin has a much more potent effect of reducing the calcium absorption

First line of defense (buffer function of the exchangeable calcium in bones)

- amorphous calcium phosphate compounds, mainly CaHPO4 -loosely bound in the bone and in REVERSIBLE equilibrium with the calcium and phosphate ions in the ECF (about .5-1% of total calcium salts of bone)

- in addition to the buffer function of the bones, the mitochondria of many tissues of the body, especially of the liver and intestine, contain a significant amount of exchangeable calcium

Hormonal Control of calcium ion concentration

-The second line of defense

Hypoparathyroidism

treatement?

-parathyroid glands do not secrete enough PTH

1) osteocytic resorption of exchangeble calcium decreases

2) the osteoclasts become almost totally inactive

**the level of calcium in the body fluids decreases. (Bone usually remains strong) --->tetany develops especially in the sensitive laryngeal muscles (this obstructs respiration --> usual cause of death

$ Decreased calcium in the blood lowers the threshold by making the cell potential relatively more depolarized (less +'s outside = more negative outside) $

-blood phosphate level increases

* PTH is sometimes used (though expensive, short acting, and antibody development)
** More often: extremely large quantities of Vitamin D w/ 1-2 grams of calcium. sometimes it is necessary to administer 1,25-digydroxycholecalciferol

Normal level of calcium in the blood

9.4 mg/dl

Primary Hyperthyroidism

-high PTH secretion
-caused mainly by tumors more frequently in women
-causes extreme osteoclastic activity in the bones
-->increased calcium and decreased phosphate

-cystic bone disease of hyperparathyroidism is called OSTEITIS FIBROSA CYSTICA

-Osteoblast activity increases --> increased levels of Alkaline phosphatase (secreted by osteoblasts to provide the phosphate needed to make bone)

What happens in Parathyroid Poisoning

-Calcium levels rise above 17 mg/dl
-calcium and phosphate rise (because kidneys can't secrete the phosphate fast enough)
** CaHPO4 crystals begin to deposit in the alveoli of the lungs, the tubules of the kidneys and the thyroid gland, KIDNEY STONES (treated with acidotic diets and acidic drugs)

Secondary Hyperparathyroidism

-high levels of PTH occur as compensation for hypocalcemia
-can be caused by a vit. D deficiency OR chronic renal disease in which the damaged kidneys are unable to produce sufficient amounts of the active form of vitamin D ---> osteomalacia (inadequate mineralization of the bones) and high levels of PTH cause absorption of the bones

Ricketswho have had their kidney's removed and are being treated by hemodialysis

* Caused by vitamin D deficiency -->calcium or phosphate deficiency
-mainly in children who do not get enough vitamin D in diet and/or do not get enough sunlight

-if the child is adequately exposed to sunlight, the 7-dehydrocholesterol in the skin becomes activated by the UV rays and forms Vitamin D3 (Cholecalciferol)
-tends to occur in the spring months b/c the stored vitamin D in the liver is sufficient to last through winter but is depleted by spring

-calcium is slightly depressed
-phosphate is GREATLY depressed

-weak osteoid is laid down when osteoblast activity is triggered. the increased PTH -->extreme osteoclast activity *WEAK BONES*

**Tetany will present in the late stages when the bones finally become exhausted of calcium (when the blood calcium falls below 7 mg/dl)

Tx. = supplying adequate calcium and phosphate in the diet AND administering large amounts of vit. D

Osteomalacia

-"Adult Rickets"

**serious deficiencies of both vitamin D and calcium occasionally occur as a result of STEATORRHEA (failure to absorb fat) because vitamin D is fat-soluble and calcium tends to pass into the feces

"Renal Rickets"

-results from prolonged kidney damage
-mainly failure of the damaged kidney to form 1,25-dihydroxycholecalciferol
-severe problem for those

Congenital hypophosphatemia

-leads to rickets and osteomalacia
-results from congenitally reduced reabsorption of phosphates by the renal tubules
**must be treated with phosphate compounds
which is why its is also call vitamin D-resistant rickets

Osteoporosis

*most common bone disease in adults
- results from diminished organic bone matrix rather than from poor bone calcification

-the OSTEOBLASTIC ACTIVITY in bone is usually less than normal
-could also be from excess osteoclastic

Causes:

1) lack of physical stress on bone
2) malnutrition to the extent that sufficient protein matrix cannot be formed
3)lack of vitamin C
4) postmenopausal lack of estrogen (* b/c estrogens decrease the number and activity of osteoclasts)
5) aging
6) Cushing's syndrome - massive quantities of glucocorticoids secreted in this disease cause decreased deposition of protein throughout the body. Increased catabolism of protein and depression of osteoblastic activity
5)

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