Download Calcium homeostasis

Calcium homeostasis
Bone remodeling and repair
• Continuous remodeling
– 5 to 7 % of total bone mass per week
– Critical for maintenance of proper structure
• Removal of calcium
Bone remodeling
• Location
– Periosteum
– Endosteum
• Remodeling units
– Osteoblasts
– Osteoclasts
• Does not occur uniformly
– Different bones/different rates
Bone remodeling
• Deposit
– Site of injury
– Strength re-enforcement
– Nutrients
• Proteins
• Vitamins (A and D)
• Minerals
Bone remodeling
• Deposit
– Osteroid seam
• New matrix deposit
– Unmineralized bone
• Calcification front
• Rate of calcification
– Local concentrations of mineral products
– Matrix proteins
– Alkaline phosphatase
Bone remodeling
• Resorption
– Break down of bone matrix
• Formation of resorption bay
– Osteoclasts
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Lysosomal enzymes
HCL
Phagocytosis of dead osteocytes
Activation triggered by T-lymphocytes
• Regulation
– Feedback loops
(Whether and when)
• Calcium homeostasis
in the blood
• Parathyroid hormone
(PTH)
– Elevates blood
calcium
concentration by
increasing
resorption
• Calcitonin
– Increase calcium
deposition by
osteoblasts
Parathyroid gland
• Embedded on the
thyroid surface
– Four in humans
• Located in the back of
thyroid glands
• Removal of thyroid
gland
– Lethal
• Removal of
parathyroid glands
– Decrease in blood
calcium level
• Tetanic convulsion
and death
• Cell composition
– Chief cells
• Secretes parathyroid
hormone
– Oxyphil cells
• Unknown functions
Oxyphil cells
Parathyroid hormone
• Essential for life
• Chemistry
– 84 AA
• Preprohormone (115 AA)
– Synthesized and converted within the Golgi zone of
the chief cells
– Proteolytic cleavage yields 90 AA prohormone
• prohormone
– Removal of 6 AA to yield mature peptide
• Released into the bloodstream via exocytosis
• Highly conserved hormone
• Short half-life
– 3-4 min
– Cleaved into two fragments
Regulation of secretion
• Blood calcium level
– Ca receptors on the parathyroid cells
• Seven-transmembrane domain receptor
– Coupled with G-protein complex
• Highly conserved
– 93 % AA homology between human and bovine
receptors
• Interaction of receptor with Ca
– Concentration- dependent conformation alteration
– Decreased cAMP production when high Ca
concentrations
– Increased cAMP production when low Ca
concentrations
• Vitamin D
– Inhibition of PTH secretion
• Genomic level
• Slow effects
– No changes in release of PTH immediately after
vitamin D treatment
Function of PTH
• Elevation of blood calcium level
– Decreased phosphate ion concentrations
– Acts on kidneys, intestines, and bones
• Effects on mineral metabolism
– Increased osteoclast activity
• Secretion of cytokines by stromal osteoblast in
response to PTH
• Demineralization of bones
• Renal excretion and reabsorption
– Increased calcium reabsporption
• Renal tubular reabsorption
– Increased phosphate excretion
(phosphaturia)
• Increased ionization of calcium
– Prevention of CaPO4 formation
– Increased Mg reabsorption
– Inhibition of Na-H exchange
• Decreased blood pH
– Inhibition of Ca binding to plasma proteins
• Absorption of calcium
– Intestine
• Increased uptake (direct)
• Effects on vitamin D metabolism (indirect)
• Control of vitamin D synthesis
– Increased 1,25-dihydrovitamin D synthesis
from vitamin D
• Kidney
• Other actions
– Increased reticulocyte and lymphocyte
mitosis
– Vasodilation
• Direct action involving specific receptor
Mechanism of action
• Interaction between
PTH and its receptor
– Increased cAMP
production
• Gs
– Activation of
phospholipase C
• Production of IP3 and
DG
– Activated by Gq
– Vitamin D-dependent
• Mobilization of Ca
from bones
• Role of vitamin D on PTH action
– Not on cAMP production
• Normal cAMP production by the bones from
vitamin D deficient mice
– Later parts of biochemical reactions
Calcitonin
• Maintenance of
blood Ca level
– Critical
– Acute elevation
• Meal
– Return to normal
shortly after
elevation
• Role of thyroid gland
– Secretion of
calcitonin
• C (clear) cells
Synthesis and metabolism
• 32 AA
– Derived from larger
prohormone
– Ring structure
• Disulfide bridge
between AA 1 and AA
7
• Isoforms
– Two
• I in combination with
II or III
• High structural similarity
– Low AA homology
– Fish calcitonin is more potent in humans
• Resists proteolytic digestion
• Higher receptor affinity