METABOLISME TULANG

Triawanti
Bagian Biokimia
 Topik
Komponen matriks tulang
Sel-sel tulang
Mineral utama tulang
Regulator metabolisme tulang
 Unsur Pembentuk Tulang
Mineral anorganik (65%)
Matriks organik (25%)
Sel osteoblast
Sel osteoklast
Sel osteosit
Air (10%)
 Unsur Pembentuk Tulang
Kolagen tulang merupakan kompnen
organik terbesar yang membentuk
dan memungkinkan tulang menahan
regangan
Anorganik atau mineral berfungsi
menahan beban tekanan
 Mineral Tulang
The most important mineral component of bone is
apatite, a form of crystalline calcium phosphate.
Apatites are complexes of cationic Ca2+ matched
by HPO4 2, CO32, OH, or F as anions.
Depending on the counter-ion, apatite can occur in
the forms carbonate apatite Ca10(PO4)6CO3, as
hydroxyapatite Ca10(PO4)6(OH)2, or fluoroapatite
Ca10(PO4)6F2.
In addition, alkaline earth carbonates also occur in
bone. In adults, more than 1 kg calcium is stored in
bone.
Struktur hidroksi apatit
 Sel-sel Tulang
Osteoblast
Osteoclast
Oseteocyt
Osteoblast and osteoclast activities in the cycle of bone
turnover
 Normal bone metabolism is the
complex sequence of bone turnover
(osteoclastogenesis) and bone
formation (osteoblastogenesis)
Physiology of bone metabolism

bone has structural and metabolic

functions
metabolic functions of bone
largely involve the homeostasis
ofcalcium and phosphate
release of calcium, or absorption
of calcium, by bone is largely
regulated by hormones and, less
so, by steroids
 Calcium
Location
bone (99%)
blood and extracellular fluid (0.1%)
intracellular (1%)
Function
calcium has a wide range of function
including
muscle cell contraction
nerve conduction
clotting mechanisms
 Calcium
Forms of calcium
bone
majority is hydroxyapatite
serum
Ca++ bound to protein (45%)
free-ionized Ca++ (45%)
bound to various anions, eg. citrate, bicarbonate (10%)
Regulation
absorption from the digestive tract
resorption from bone
resorption in the kidneys
 Calcium
Dietary requirements
2000 mg/day for lactating women
1500 mg/day for pregnant women,
postmenopausal woman, and patients with a
healing bone fracture
1300 mg/day for adolescents and young adults
750 mg/day for adults
600 mg/day for children
Dysfunction
hypercalcemia
hypocalcemia
Gambar absorbsi Ca yang distimulasi oleh 1,25 (OH)2D3
 Phosphate
Location
bone (86%)
blood and extracelluar fluid (0.08%)
intracellular (14%)
Function
key component of bone mineral
important in enzyme systems and molecular
interactions
Forms of phosphate
bone
majority is hydroxyapatite
serum
mostly inorganic phosphate (H2PO4-)
 Phosphate
Regulation
plasma phosphate is mostly unbound
and reabsorbed by the kidney
may be excreted in urine
elevated serum phosphate can lead to
increased release of PTH and bone
resorption
Dietary intake
1000-1500 mg/day
Regulators of bone metabolism

Hormones
PTH
Calcitonin
Sex Hormones (eg. estrogen, androgens)
Growth Hormone
Thyroid Hormones
Steroids
Vitamin D
Glucocorticosteroids
 Properties of bone
metabolism
Bone mass
bone mass is the measure of bone
tissue present at the end of skeletal
maturity
represents both its volume and size, as
well as the density of the mineralized
tissue
peak bone massoccurs between ages
16 and 25
greater in men and African Americans
 Properties of bone
metabolism
Bone loss
bone mass decreases by 0.3 to 0.5% per
year after skeletal maturity
further decreases by 2-3% per year for
untreated women during the 6th-10th
years after menopause
rate of bone loss can be modulated by
structural and metabolic factors
 Hormon Paratiroid
Structure
84 amino acid peptide
Origin
synthesized and secreted from chief
cells in the four parathyroid glands
Net effect
increases serum calcium
decreases serum phosphate
 Hormon Paratiroid
Mechanism
bone
PTH stimulates osteoblasts to secrete IL-1,
IL-6 and other cytokines toactivate
osteoclasts and increase resorption of bone
Increases osteoblast production ofM-CSF
(macrophage colony-stimulating factor) and
RANKL, which increases number of
osteoclasts.
Paradoxically, osteoclasts do not express
receptor for PTH
 Hormon Paratiroid
Lanjutan mekanisme
kidney
stimulates enzymatic conversion of 25-(OH)-vitamin
D3converted to1,25-(OH)2-vitamin D3(active
hormone form) which:
increases resorption of Ca++ in kidney (increasing serum
Ca++)
increases excretion of PO4- from kidney (decreasing serum
phosphate)
intestine
no direct action
indirectly increase Ca++ absorption by
activating1,25-(OH)2-vitamin D3
 Hormon Paratiroid
Dysfunction
PTH-related protein and its receptor
have been implicated in metaphyseal
dysplasia
Parathyroid hormone-related protein
(PTHrP) has related effects to PTH as
it binds to the same receptors on
osteoblasts and renal cells to
increase serum calcium
 Calcitonin
Structure
32 amino-acid peptide hormone
Origin
produced by clear cells in the
parafollicles of thethyroid gland (C
cells)
Net effect
limited role in calcium homeostasis
inhibitnumber and activity of
osteoclasts
 Calcitonin
Function
bone
inhibits osteoclastic bone resorption by decreasing number and
activity of osteoclasts
osteoclast have receptor for calcitonin
Inc. serum Ca > secretion of calcitonin > inhibition of
osteoclasts > dec. Ca (transiently)
Dysfunction
secreted by medullary thyroid tumors and mulitple
endocrine neoplasia type II tumors
Recombinant calcitonin used to treat Paget disease,
osteoporosis, and hypercalcemia in malignancy
 Vitamin D
Structure
fat soluble secosteroid (steroid with a 'broken ring')
Origin
produced by skin when exposed to sunlight (UVB-
generated Vitamin D)
dietary intake (lipid-soluble vitamin D3)
active metabolite1,25-(OH)2-vitamin D3 formed by two
hydroxylations in the liver and kidney, respectively
Net effect
maintains normal serum calcium levels by activating
osteoclasts for bone resorption and increasing intestinal
absorption of calcium(increase serum Ca++)
promotes the mineralization of osteoid matrix
 Vitamin D
Function
liver
activated-vitamin D3converted to25-(OH)-vitamin D3
kidney
25-(OH)-vitamin D3converted to1,25-(OH)2-vitamin
D3(active hormone form)
activated by
increased levels of PTH
decreased levels of serum Ca++, P
1,25-(OH)2-vitamin D3(active hormone form)can be
inactivated to 24,25-(OH)2-vitaminD3
inactivity occurs with:
decreased levels of PTH
increased levels of serum Ca++, P
vitamin D parallels that of PTH by increasing
reabsorption of Ca in the kidneys
 Vitamin D
bone
1,25-(OH)2-vitamin D3 stimulates
terminal differentiation of osteoclasts
when osteoclasts mature they do not
respond to 1,25-(OH)2-vitamin D3and
respond mostly to cytokines released by
osteoblasts
1,25-(OH)2-vitamin D3promotes the
mineralization of osteoid matrix
produced by osteoblasts
 Vitamin D
Dysfunction
Vitamin D deficiency causes
osteomalaciaand rickets
phenytoin (dilantin) causes impaired
metabolism of vitamin D
 Estrogen
Structure
D ring steroid hormone
Origin
predominantly in the ovaries
synthetic forms available
Net effect
preventsbone loss by decreasing the
frequency of bone resorption and
remodeling
 Estrogen
Function
alone, because bone formation and
resorption are coupled, it also indirectly
decreases bone formation
leads to an increase in bone density of
the femoral neck and reduces the risk of
hip fracture
most important sex-steroid for peak
bone mass attainment in both men and
women
 Estrogen
secondary effects
increases risk of
heart disease
breast cancer
decreases risk of
hip fracture
endometrial cancer (if combined with cyclic
progestin)
laboratory
will see a decreases in
urinary pyridoline
serum alkaline phosphatase
 Estrogen
Therapeutic estrogen
outcomes
decreases bone loss if started within 5-10
years after onset of menopause
significant side effects so risk/benefit ratio
must be evaluated
gains in bone mass usually limited to an
annula increase of 2-4% for the first 2 years
of therapy
 Hormon Tiroid
Function
regulates skeletalgrowth at the
physisby stimulating
chondrocyte growth
type X collagen synthesis
alkaline phosphatase activity
thyroid hormones increase bone
resorption and can lead toosteoporosis
large doses of therapeutic thyroxine can
mimic this process and cause osteoporosis
 Growth Hormone
Function
increases serum calcium by
increased absorption in intestine
decreasing urinary excretion
function is interdependent with insulin, somatomedins, and growth
factors (TGF-B, PDGF, mono/lyphokines)

Gigantism :
oversecretion or increasedresponse to
growth hormone effecting theproliferative
zoneof the growth plate
 What is Growth?
Growth is an increase in size of a
tissue/organism due to
- increase in cell size (hypertrophy)
- increase in number of cells
(hyperplasia)
- increase in extracellular matrix around
cells
hypertrophy

hyperplasia
Growth Hormone
(GH; Somatotropin)
The major hormone regulating growth
in the body is growth hormone (GH;
somatotropin).
Actions of Growth Hormone:
- increases skeletal growth
- increases muscular growth
- increases amino acid uptake and
protein synthesis
- increased use of lipids for energy
- decreased storage of carbohydrates
Role of Somatomedins in GH Actions
the GH/IGF Axis
The effects of GH on skeletal and
muscular growth appear to be due to the
activity of somatomedins, or insulin-like
growth factors (IGF-1 and IGF-2)
processed in the liver.
GH acts on the liver, and some other
tissues, to increase the production of
IGFs.
IGFs then enter the circulation and act
on target tissues to enhance growth.
 IGF Receptors
IGFs bind to specific receptors (type-I IGF
receptor and the insulin receptor) to
stimulate growth.
The type-I IGF receptor is similar to the
insulin receptor, with intrinsic tyrosine
kinase activity.
Binding of IGFs to their receptors results
in phosphorylation of insulin-responsive
substrates (IRSs), which stimulate
extracellular tissue
domains
(ligand binding)
growth and differentiation.
plasma membrane

tyrosine kinase Growth and

domains phosphorylation of IRSs differentiation
 Some Observations in Knockout
Mice:
IGF-II
Gene knockout experiments can
create mice which lack expression of
certain genes.
Knockout of IGF-II gene results in
slower fetal development, with low
birth weights. However, after birth
these mice grow at normal rates.
This finding suggests that IGF-II is
an important fetal growth factor,
with unclear role in growth after
birth.
Some Observations in Knockout
Mice:
IGF-I
Knockout of the IGF-I gene also
results in slow fetal development
and low birth weights.
However, these mice also display
marked lack of growth after birth
as well.
Thus, IGF-I is important for
growth at all stages of
development (before and after
birth).
 Steroid
Function
increase bone loss by
decreasing Ca++ absorptionin intestine
through a decrease in binding proteins
decreasing bone formation(cancellous
more so than cortical bone) by
decreasing collagen synthesis
inhibiting osteoblast activity
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