dr. Susila Sastri M.Biomed
Bahagian Biokimia
FK-UNAND
• extracellular calcium (Ca2+ : 5 mmol/L and
is very rigidly controlled.
• amounts of calcium: associated with
intracellular organelles such as
mitochondria and the endoplasmic
reticulum, the intracellular concentration of
free or ionized calcium (Ca2+ ) is very low:
0.05–10 mmol/L.
Struktur tulang
 Bone : connective tissue, substantial metabolic
activity.
 type 1 collagen: the major protein (90%)
 calcium-rich crystals : hydroxyapatite
(Ca10[PO4]6[OH]2)
 Microarchitecture: reservoir of calcium
 Osteoid: noncalcified organic matrix
Cristal Apatite
 Complexes of cationic Ca2+ matched by
HPO4 2–, CO32–, OH–, or F– as anions.
 carbonate apatite Ca10(PO4)6CO3
 hydroxyapatite Ca10(PO4)6 (OH)2
 fluoroapatite Ca10(PO4)6F2
 In adults, more than 1 kg calcium is stored
in bone.
Calcium circulation
 ionized Ca2+: active form (50% of total
calcium).
 protein-bound: bound to negatively
charged albumin (40%); Ca2+ buffers
 Complexed : citrate and phosphate:
(10%).
Fungsi Ca
• Bone component: 1–1.5 kg Ca2+ most of
which (about 98%) is located in the
mineral substance of bone
• Signaling substance: Ca2+ ions act as
second messengers in signal
transduction pathways:
– exocytosis
– muscle contraction
– cofactors in blood coagulation
• Enzymes Co –factor
• Proteins bind Ca2+ via oxygen ligands,
Enzymes and proteins regulated by
calcium or calmodulin.
Factors influencIng calcium homeostasis
 Parathyroid hormone (PTH)
 Vitamin D
 25-hydroxycholecalciferol (25(OH)D3) is
the main liver storage form of vitamin D
 1,25(OH)2D3 increases serum
concentrations of calcium and phosphate
 Calcitonin inhibits osteoclastic bone
resorption
Calcium effects
• calcium sensors : biochemical effects of Ca2+
in the cytoplasm (Ca2+ binding proteins) :
annexins, calmodulin, and troponin C in
muscle
• Calmodulin: Binding of four Ca2+ ions
• Ca2+ ions : regulate the activity of enzymes,
ion pumps, and components of the
cytoskeleton.
Bone remodeling
• Mineralization : Deposition of Ca2+ in bone and Ca2+
•
•
•
•
•
mobilization from bone are regulated by at least 15
hormones and hormone like signaling substances.
These mainly influence the maturation and activity of
bone cells.
Osteoblasts : deposit collagen, Ca2+ and phosphate,
and thereby create new bone matter
Osteoclasts : secrete H+ ions and collagenases that
locally dissolve bone (bone remodeling).
Osteoblasts and osteoclasts mutually activate each
other by releasing cytokines and growth factors.
bone formation and bone breakdown : balance.
Bone remodeling
Calcitonin
• Calcitonin: A polypeptide hormone (32amino acid) residues that is synthesized in the
parafollicular cells (C cells) of the thyroid
gland.
• Calcitonin is secreted in response to elevated
blood Ca2+ levels.
• IP3: Inositol 1,4,5-trisphosphate (inositol
trisphosphate); a second messenger
• IP3 bind to receptors on the endoplasmic
reticulum (ER) to cause the rapid efflux of Ca2+
from the ER into the cytoplasm.
Parathyroid hormone
• PTH: 84-amino acid polypeptide hormone
that is synthesized in the parathyroid gland
and is secreted in response to low blood
Ca2+ levels.
• PTH: increase the Ca2+ concentration in the
blood by stimulating osteoclast formation
and activity, thus releasing bone calcium
and phosphate into the blood
Vitamin D
• Vitamin D3: a secosteroid formed by the
action of UV light on 7-dehydrocholesterol.
• The active form of vitamin D: hormone 1,25dihydroxycholecalciferol (calcitriol),
formed in the kidney in response to
elevated PTH levels.
• It binds to nuclear receptors in intestine,
bone, and kidney to activate the expression
of calcium-binding proteins.
Maintaining bone mass - the bone remodeling cycle.
Resorption and formation of bone by osteoclasts and osteoblasts is coupled
• The Ca2+ selective hormones calcitriol, parathyroid
•
•
•
•
•
hormone, and calcitonin influence this interaction in
the bone cells.
Parathyroid hormone promotes Ca2+ release by
promoting the release of cytokines by osteoblasts.
Cytokines: stimulate the development of mature
osteoclasts from precursor cells
Calcitonin inhibits this process. At the same time,
it promotes the development of osteoblasts
Osteoporosis: women following the menopause
(reduction in estrogen levels)
Estrogens normally: inhibit the stimulation of
osteoclast differentiation by osteoblasts. If the effects
of estrogen decline, the osteoclasts predominate and
excess bone removal occurs.
Calcitriol
• steroid hormone calcitriol in bone are complex.
– promotes bone formation by stimulating osteoblast
differentiation, important in small children, in whom
calcitriol deficiency can lead to mineralization
disturbances
– increases blood Ca2+ levels through increased Ca2+
mobilization from bone.
• An overdose of vitamin D (cholecalciferol), the
precursor of calcitriol, can therefore have unfavorable
effects on the skeleton similar to those of vitamin
deficiency (hypervitaminosis)
Calcium homeostasis
• Ca2+metabolism: balanced in healthy adults.
• 1 g Ca2+ : taken up per day, about 300 mg of which
is resorbed.
• The same amount is also excreted again.
• The amounts of Ca2+ released from bone and
deposited in it per day are much smaller.
• Milk and milk products, especially cheese, are
particularly rich in calcium.
CLINICAL CORRELATION
• Malignancies or hyperparathyroidism : Hypercalcemia :
kidney stones
• Osteoporotic : Estrogen decrease
• Genetic conditions:
• familial hypocalciuric hypercalcemia
• hyperparathyroidism.
• Osteomyelitis
• osteosarcoma