Transcript Metabolizam kalcija i fosfata, vitamin D, paratireoidni hormon

Parathyroid Hormone,
Calcitonin, Calcium and
Phosphate Metabolism
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
Calcium and Phosphate
Regulation in the ECF and Plasma
Ca+2 in extracellular fluid (ECF) – 2,4 mmol/L
 normally precisely regulated (few %)
 key role of Ca+2 in many physiologic processes:
muscle contraction, blood clotting, transmission of
nerve impulses
 hypercalcemia – depression;/ hypocalcemia –
excitetion (tetany)
 0.1% Ca+2 in ECF, 1% in cells, rest is stored in
bones

 85%
of body's phosphate is stored in bones
 14-15% in cells,  1% in ECF
 concentration is not nearly as well regulated
as calcium
 same factors that regulate calcium
Calcium in the Plasma and
Interstitial Fluid (IF)
 present
a)
b)
c)
in three forms :
41% - combined with plasma proteins
9% - combined with anionic substances
(citrate and phosphate)
50% - ionized
 ionic
calcium is the form that is important for
most functions of calcium in the body
Inorganic Phosphate in the ECF

in the plasma is mainly in two forms :
HPO42- - 1.05 mmol/L
b) H2PO4- - 0.26 mmol/L
a)
 concentration depends on pH of plasma
 total quantity of phosphate is expressed in
terms of phosphorus per liter of blood
 1.3 mmol/L (depending on age)
Nonbone Physiologic Effects of
Altered Calcium and Phosphate
Concentrations
 hypocalcemia
causes nervous system
excitement ( permeability to Na+)
 tetany occurs when calcium decreases to 1.5
mmol/L, and death when it is 1 mmol/L
 hypocalcemia : dilatation of heart, changes
in enzyme activities, increased membrane
permeability of some cells, impaired blood
clotting – nonphysiological decrease
Hypercalcemia
 nervous
system becomes depressed
 lack of appetite and constipation
 decreases the QT interval of the heart
 depressive effects begin to appear when
calcium rises above 3.0 mmol/L, they can
become marked above 3.8 mmol/L
Absorption and Excretion of
Calcium and Phosphate
 daily
intake is about 1000 mg/day each for
calcium and phosphorus (25 mmol) – 1L of
milk
 90% of daily intake of calcium is excreted in
feces
 almost all the dietary phosphate is absorbed
into the blood from the gut and later excreted
in the urine
 kidney
filers calcium (ionized and combined
with anions)
 renal tubules reabsorb 99 percent of the
filtered calcium
 renal phosphate excretion is controlled by an
overflow mechanism (critical value of about
1 mmol/L – no phosphate is lost in the urine)
Bone and Its Relation to ECF
Calcium and Phosphate



bone = organic matrix + calcium salts
compact bone: 30% matrix, 70% salts
organic matrix :
a)
b)

90-95 % collagen fibers (tensile strength)
5-10 % ground substance (ECF +
proteoglycans, chondroitin sulfate and
hyaluronic acid)
bone salts: calcium and phosphate
Bone Salts
 Ca10(PO4)6(OH)2
– shaped like long, flat plate
 relative ratio of Ca/P 1.3-2.0
 ions Mg2+, Na+, K+ & HCO3 many ions of many types of ions
(transuranic elements and heavy metals)
 osteogenic sarcoma (bone cancer)
 hydroxyapatite
Tensile and Compressional
Strength of Bone
 compact
bone is composed of repeating
periodic segments of collagen
 hydroxyapatite crystals bound tightly to it –
prevents "shear" in the bone
 collagen fibers – tensile strength
 calcium salts – compressional strength
Precipitation and Absorption of
Calcium and Phosphate in Bone
 concentrations
of calcium and phosphate
ions in ECF are considerably greater than
those required to cause precipitation of
hydroxyapatite
 pyrophosphate – inhibitor which prevent
precipitation
Bone Calcification
osteoblasts produce osteoid (collagen molecules +
ground substance)
 calcium salts begin to precipitate on the surfaces
of the collagen fibers, forming minute nidi
 mixture of amorphous compounds (noncrystalline)
salts of Ca & P, converted into the hydroxyapatite
crystals over a period of weeks or months
 few percent may remain permanently in the
amorphous form (important role)
 mechanism is not fully understood

Precipitation of Calcium in
Nonosseous Tissues
 arteriosclerosis
 degenerating
tissues
 old blood clots
Calcium Exchange Between
Bone and ECF
 fast
correction of plasma Ca concentration
 exchangeable calcium – in equilibrium with
the calcium ions in the ECF – rapid
buffering mechanism
 in all tissue cells (liver and gastrointestinal
tract) & in the bone (amorphous calcium
salts)
Deposition and Absorption of
Bone
 osteoblasts
(on outer surfaces of bones and in
bone cavities):
 active on 4% of all surfaces in an adult
 osteoclasts :
 large, multinucleated cells (50 nuclei)
 derivatives of monocytes, phagocytic
 active on less than 1% bone surfaces
 PTH controls bone absorption by
osteoclasts
Absorption of Bone


osteoclasts send out villus-like projections
toward the bone (ruffled border) & secrete:
a)
proteolytic enzymes – organic matrix
b)
acids (citric, lactic acid) – bone salts
PTH stimulates osteoclast activity and bone
resorption, but through indirect mechanism



PTH binds to receptors on adjacent
osteoblasts
osteoblasts release cytokines:
osteoprotegerin ligand (OPGL or RANKL)
OPGL activates receptors on preosteoclast
cells  mature multinucleated osteoclasts
 development of ruffled border (release of
enzymes and acids)






osteoblasts also produce osteoprotegerin
(OPG, also called OCIF)
OPG inhibits bone resorption
OPG acts as a "decoy" receptor binding to
OPGL and preventing its actions
vitamin D and PTH inhibit OPG production
and stimulate OPGL formation
estrogen stimulates OPG production
used for treatment


bone deposition and absorption are
normally in equilibrium – total mass of
bone remains constant.
concentrated mass of osteoclasts  tunnel
in diameter 0,2-1 mm and several mm long
 tunnel is invaded by osteoblasts  new
bone begins to develop




new bone being laid down in successive
layers of concentric circles (lamellae)
deposition of new bone ceases when the
bone begins to encroach on the blood
vessels supplying the area
haversian canal, is all that remains of the
original cavity
osteon
Value of Continual Bone
Remodeling
 bone
strength in proportion to bone stress
 shape of the bone can be rearranged
 replacement of old organic matrix
 bone
is deposited in proportion to the
compressional load (athletes & cast)
 repair of fracture activates osteoblasts
 callus, rings
Gavril Ilizarov
Vitamin D
 potent
effect to increase calcium absorption
from the intestinal tract
 vitamin D itself is not the active substance
 must first be converted into:
1,25-dihydroxycholecalciferol
 7-dehydrocholesterol
+ ultraviolet rays (in
the skin) – cholecalciferol (vitamin D)
a) precise control
b) spearing vitamins
Formation of 1,25Dihydroxycholecalciferol
 proximal
tubules of the kidneys
 the most active form of vitamin D
 in the absence of the kidneys, vitamin D
loses almost all its effectiveness
 requires PTH
a) precise control
b) spearing vitamins
Actions of Vitamin D
 intestines,
kidneys, bones
 intestines : hormone,  absorption of Ca by
 formation of calbindin, a calcium-binding
protein
 + Ca ATP-aza & alkaline phosphatase in the
brush border
  absorption of P by the intestines, direct
effect and secondarily from this hormone's
action on calcium absorption
 reabsorption of Ca & P by the
epithelial cells of the renal tubules
 kidneys:
 bone:
quantities of vitamin D –
absorption of bone ( Ca transport)
 smaller quantities of vitamin D – promotes
bone calcification (increase absorption from
the intestines;  Ca transport in opposite
direction)
 extreme
Parathyroid Hormone
 powerful
mechanism for controlling ECF
Ca & P concentrations
 regulates intestinal reabsorption and renal
excretion
 regulates exchange between the ECF and
bone of these ions


increased secretion causes rapid absorption
of calcium salts from the bones –
hypercalcemia
hypofunction of the parathyroid glands –
hypocalcemia (tetany)





normally – 4 parathyroid glands in humans
located immediately behind thyroid gland
6 x 3 x 2 mm, appearance of dark brown fat
danger of removal during thyroid operations
(2(3) out of 4 – OK)
chief cells (majority) and oxyphil cells
(function unknown, absent in many animals
and in young humans)
Chemistry of PTH




PTH has been isolated in a pure form
preprohormone (110 AA)  prohormone
(90 AA)  PTH itself (84 AA)
smaller compounds have also been isolated
that exhibit full PTH activity
kidneys rapidly remove big PTH within
minutes but fail to remove many of the
fragments for hours
Effect of PTH on Ca & P
Concentrations in ECF
Effect of PTH on Ca & P
Concentrations in Plasma





phosphate concentration falls more rapidly
than the calcium rises
both reach a plateau in about 4 hours
increase Ca & P absorption from bone
decrease excretion of Ca by kidneys
increase renal P excretion
PTH Increases Ca & P
Absorption from Bone
 rapid
phase: activation of the already
existing osteocita (begins in minutes)
 much slower phase: proliferation of the
osteoclasts (requiring several days or even
weeks)
Rapid Phase – Osteolysis
membrane system – separates the
bone itself from ECF
 bone fluid – small amount between
osteocytic membrane and bone
 pumping of Ca ions from bone fluid into
ECF – osteocytic pump
 osteocytic
Rapid Phase – Osteolysis
 bone
fluid calcium concentration falls even
lower  absorbed of Ca & P from the bone
– osteolysis
 PTH strongly activates calcium pump (
Ca permeability of the bone fluid side of the
osteocytic membrane)
Slow Phase of Bone Absorption


PTH activates osteoblasts and osteocytes
which send secondary "signals" to the
osteoclasts (OPGL)
1)
immediate activation of the osteoclasts
that are already formed
2)
formation of new osteoclasts
osteoclastic resorption of bone can lead to
weakened bones and secondary stimulation
of the osteoblasts
PTH Decreases Ca Excretion and
Increases P Excretion by Kidneys
 increased
P excretion is based on diminish
proximal tubular reabsorption of P ions
 simultaneous increase in renal tubular
reabsorption of Ca
 PTH increases reabsorption of Mg & H, and
diminish reabsorption of Na, K, AA
Control of PTH Secretion by Ca
Ion Concentration
 PTH increases reabsorption of Ca & P from
the intestines
 cAMP mediates the effects of PTH
 Ca concentration controls secretion of PTH
 parathyroid glands become greatly
enlarged in rickets (5x) in pregnancy,
and during lactation
Decrease in PTH Secretion
 excess
quantities of Ca in the diet
 increased vitamin D in the diet
 bone absorption caused by factors other
than PTH (immobilization)
 changes
in ECF Ca ion concentration are
detected by a calcium-sensing receptor
(CaSR) in parathyroid cell membranes
 CaSR is a G protein-coupled receptor
 stimulated by calcium ions, activates
phospholipase C ( in IP3 and DAG)
 stimulation of Ca release from intracellular
stores  decreases PTH secretion
Calcitonin
 synthesis
and secretion of calcitonin occur
in the parafollicular cells, or C cells of
thyroid gland (0,1% of the human thyroid
gland, remnants of ultimobranchial glands)
 effects opposite to those of PTH
 32-amino acid peptide
  ECF Ca ion concentration – primary
stimulus for calcitonin secretion
Mechanism of Calcitonin Action

absorptive activities of the osteoclasts
  osteolytic effect of osteocytic membrane
  formation of new osteoclasts
 minor
effects on calcium handling in the
kidney tubules and the intestines
 calcitonin has bigger effect in children and
certain diseases (Paget) than in adult human
Summary of Control of Ca Ions
line of defense – buffer function of the
exchangeable calcium in bones –
amorphous compounds (Ca HPO4)
 + mitochondria of the liver and intestine
 first
 second
line of defense – hormonal control
Pathophysiology
 Hypoparathyroidism
( PTH secretion)
 osteocytic resorption of Ca + osteoclasts
inactivity   Ca  tetany (laryngeal muscles)
 extremely large quantities of vitamin D or giving
PTH (expensive, short-acting, antibodies)

 Hyperparathyroidism
(primary & secondary)
ordinarily tumor (in women because pregnancy)
 extreme osteoclastic activity   Ca &  P
 fractures, decalcification, muscle weakness,

 Rickets
 Ca (slightly) & P (greatly) in ECF, usually
caused by lack of vitamin D
 occur in spring months after depletion of stores
 compensatory increase in PTH secretion causes
extreme osteoclastic absorption of the bone
 tetany occurs in later stages – death
 treatment : vitamin D + Ca & P in the food
 steatorrhea – osteomalacia (adult rickets)
 renal rickets – failure of the damaged kidneys
to form 1,25-dihydroxycholecalciferol

 Osteoporosis
most common of all bone diseases in adults
 especially in old age
 decreased bone matrix
 osteoblastic activity is usually less than normal
– osteoid deposition is depressed
 lack of physical stress on the bones because of
inactivity, malnutrition, lack of vitamin C,
postmenopausal lack of estrogen secretion, old
age ( hGH), Cushing's syndrome (
glucocorticoids)

 treatment:
 antiresorptive
drugs:
bisphosphonates (Fosamax, Actonel & Boniva)
 estrogen substitution therapy
 SERMs (raloxifene, Evista) – osteoclasts
 calcitonin
 inhibitors of RANKL (monoclonal antibody,
Denosumab)

 anabolic
drugs:
teriparatide (Forteo) – recombinant PTH
 calcium salts (carbonates, citrates, lactates)
 sodium-fluoride

Physiology of the Teeth
 teeth
cut, grind, and mix the food eaten
 forces: 250-450N & 650-900N
 occlusion – fitting of upper set of teeth with
the lower
 major
functional parts: enamel, dentin,
cementum and pulp
 another division: crown, neck and root
Enamel
 outer
surface of the tooth; ameloblasts
 formed before eruption of the tooth
 composed of large and dense crystals of
hydroxyapatite with adsorbed Mg, Na, K +
insoluble protein fibers (similar to keratin)
 extremely hard and resistant to acids,
enzymes, and other corrosive agents
Dentin
 main
body of tooth, strong, bony structure
 hydroxyapatite crystals much denser than in
bone, embedded in a strong meshwork of
collagen fibers
 does not contain: osteoblasts, osteocytes,
osteoclasts, spaces for vessels or nerves
 odontoblasts: formation and nurishment
 calcium salts: compressional forces
 collagen: toughness and tensional forces
Cementum
 bony
substance secreted by cells of the
periodontal membrane – lines tooth socket
 collagen fibers pass directly from jaw bone
through periodontal membrane into
cementum
 increases in thickness and strength with age
Pulp
 filling
pulp (tooth) cavity
 composed of connective tissue, nerve fibers,
blood vessels, and lymphatics
 odontoblasts – cells lining the surface of the
pulp cavity
 during the formative years lay down dentin
 send projections into small dentinal tubules
that penetrate all the way through the dentin
Dentition
 humans
and most other mammals develop
two sets of teeth during a lifetime
 deciduous or milk teeth (20)


erupt between 7th month and 2nd year
last until 6 th and 13 th year
 permanent
teeth (32)
Formation of the Teeth
 invagination
of the oral epithelium into the
dental lamina and development of a toothproducing organ
 epithelial cells above form ameloblasts
(enamel)
 epithelial cells below invaginate upward
into the middle of the tooth to form the pulp
cavity and the odontoblasts (dentin)
Eruption of Teeth
 cause
of "eruption" is unknown
 most likely theory is that growth of the
tooth root and the bone underneath the tooth
progressively shoves the tooth forward
Development of Permanent Teeth
 when
each permanent tooth becomes fully
formed, it pushes outward through the bone
 erodes the root of the deciduous tooth and
eventually causes it to loosen and fall out
Metabolic Factors
 thyroid
and growth hormones
 availability of Ca & P in the diet
 amount of vitamin D
 rate of PTH secretion
Mineral Exchange in Teeth
 salts
composed of hydroxyapatite with
adsorbed carbonates and various cations
 new salts are constantly being deposited
while old salts are being reabsorbed
 deposition and reabsorbtion – in dentin and
cementum, limited extent in enamel (saliva)
 rate of exchange in dentin 3x slower than in
bone
Dental Abnormalities
1)
2)
caries (erosion of the teeth)
malocclusion (failure of the projections of
the upper and lower teeth to interdigitate
properly)
1) Caries
 action
of bacteria on the teeth
(Streptococcus mutans)
 deposit of plaque (film of saliva and food)
 dependance on carbohydrates (form acids
(lactic) and proteolytic enzymes)
 acids – slow dissolvement of calcium salts
 enamel of the tooth is primary and most
important barrier to development of caries
 small
amounts of fluorine develop enamel
that is more resistant to caries
 fluorine does not make the enamel harder
 fluorine ions replace many of hydroxyl ions
in hydroxyapatite crystals, which in turn
makes enamel several times less soluble
 fluorine may also be toxic to the bacteria
 fluorine promote deposition of calcium
phosphate to "heal" the enamel surface
2) Malocclusion
 hereditary
abnormality
 teeth of one jaw grow to abnormal positions
 teeth do not interdigitate properly and
therefore cannot perform their normal
grinding or cutting action adequately
 pain in mandibular joint and deterioration of
the teeth
 treatment: continuous force on teeth
FIGURE 1. Phosphorus homeostasis in normal humans
Berndt, T. et al. Physiology 24: 17-25 2009;
doi:10.1152/physiol.00034.2008
Copyright ©2009 American Physiological Society
FIGURE 4. Adaptations to changes in dietary phosphate
Berndt, T. et al. Physiology 24: 17-25 2009;
doi:10.1152/physiol.00034.2008
Copyright ©2009 American Physiological Society