Biokimia Tulang

Bone is a
mineralized
connective
tissue
Biochemistry Department
Cells of Bone Tissue
Bone contains both organic and inorganic material.

The organic matter is mainly protein. The principal
proteins of bone are listed in Table 489;
type I
collagen is the major protein, comprising 9095%
of the organic material.
Type V collagen is also present in small amounts,
as are a number of noncollagen proteins, some of
which are relatively specific to bone.
The inorganic or mineral component is mainly crystalline

hydroxyapatiteCa10(PO4)6(OH)2along with sodium,
magnesium, carbonate, and fluoride; approximately 99% of the
bodys calcium is contained in bone. Hydroxyapatite confers on
bone the strength and resilience required by its physiologic
roles.
Bone is a dynamic structure that undergoes

continuing cycles of remodeling, consisting of
resorption followed by deposition of new bone tissue.
This remodeling permits bone to adapt to both
physical (eg, increases in weight-bearing) and
hormonal signals.
K
m
d
m
d
(
k
Inorganic components make up g
65% of bone by mass, and
s
consist of hydroxyapatite
k
(calcium phosphate + calcium b
carbonate), a mineral salt that
is largely calcium phosphate, a
k
which accounts for the
t
hardness and compression
resistance of bone
Chemical Composition of Bone
Organic components of bone

include cells (osteoblasts,
osteocytes, and osteoclasts)
and osteoid (ground substance
and collagen fibers), which
contribute to the flexibility and
tensile strength of bone.
Osteoblas adalah
sel sel-sel
tulang
bangunan
.
Osteosit adalah
tulang
dewasa berkembang
ketika osteoblas terperangkap dalam kekosongan .
Mensintesis dan komponen
secreteorganic yang dibutuhkan untuk
membangun EC matriks .

The extracellular
matrix is about 25%
water, 25% collagen
fibers and 50%
crystalized minerals.
Osteoblasts are bone

building cells.
Synthesize and
secreteorganic
component needed
to build EC matrix.
Osteocytes are
mature bone cells
develop when
osteoblasts are
trapped in lacuna.
Osteoblasts
bone-forming
cells
Osteocytes
mature bone
cells
Osteoclasts
large cells
that resorb or
break down
bone matrix
Osteoid
unmineralize
d bone matrix
composed of
proteoglycans
,
glycoproteins,
and collagen
Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings

Osteoclasts are
multicellular
structure
responsible for
resorption of the
breakdown of the
EC matrix termed
resorption. Found
in the periosteum.
Osteogenic cells
are stem cells
found in the inner
portion of the
periosteum.
Osteogenic cells
are the only ones
undergoing cell
division.
Chemical Composition of Bone:

Inorganic
Hydroxyapatites, or mineral
salts
Sixty-five percent of bone by

mass
Mainly calcium phosphates
Responsible for bone hardness
and its resistance to
Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings
Osteoclasts
Resorbe
bone matrix from sites where it is

deteriorating or not needed
Digest bone matrix components
Focal decalcification and extracellular
digestion by acid hydrolases and uptake of
digested material
Disappear after resorption
Assist with mineral homeostasis
Chemistry of the bone

Matrix
Mineral
Matrix - osteoid
Collagen
type I and IV
Layers of various orientations (add to the
strength of the matrix)
Other proteins 10% of the bone protein
Direct formation of fibers

Enhance mineralization
Provide signals for remodeling
Mineral
A calcium
phosphate/carbonate compound
resembling the mineral hydroxyapatite
Ca10(PO4)6(OH)2
Hydroxyapatite crystals
Imperfect
Contain Mg, Na, K
Mineralization of the bone

Calcification
occurs by extracellular deposition

of hydroxyapatite crystals
Trapping
of calcium and phosphate ions in

concentrations that would initiate deposition of
calcium phosphate in the solid phase, followed by
its conversion to crystalline hydroxyapatite
Mechanisms
calcification
exist to both initiate and inhibit
Bone remodeling process

Proceeds
in cycles
first resorption than
bone formation
The calcium content of
bone turns over with a
half-life of 1-5 years
Bone remodeling process
Bone remodeling cycle (1)

Endosteal sinus
Monocyte
Pre-osteoclast
Pre-osteoblast
Osteoclast
Osteocyte
Macrophage
Osteoblast
Bone-lining cell
Osteoid
New bone
Old bone
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Endosteal sinus
Monocyte
Pre-osteoclast
Pre-osteoblast
Osteoclast
Macrophage
Osteoblast
Bone-lining cell
Osteocyte
Osteoid
New
bone
Old
bone

Pre-osteoblasts
Monocytes
Osteoclasts
Osteoblasts
Osteocytes

Bone Deposition and

Resorption
Ca2+ and phosphate concentrations are affected by:
Bone formation and resorption.
Intestinal absorption of Ca2+ and P043-.
Urinary excretion.
Osteoblasts:
Secrete an organic matrix of collagen proteins.
Deposit hydroxyapatite crystals.
Osteoclasts:
Secrete enzymes to dissolve hydroxyapatite.
Formation and resorption of bone occur constantly at rates
determined by osteoblasts and osteoclasts.
Bone Deposition and Resorption

(continued)
Bone resorption occurs when an osteoclast attaches to the

bone matrix and forms ruffled membrane.
Osteoclast secretes products that dissolve both Ca2+ and P043- ;
and digest the matrix.
Transport of H+ by H+ ATPase pump in ruffled border.
Cl- channel allows Cl- to flow to H+ to maintain electrical neutrality.
Protein matrix digested by cathepsin K.

Cytoplasm prevented from becoming to basic by a Cl-/HC03- pump.

Bone Deposition and Resorption

(continued)

Bone Resorption

Figure 4812. Schematic illustration of some aspects of the

role of the osteoclast in bone resorption. Lysosomal enzymes
and hydrogen ions are released into the confined
microenvironment created by the attachment between bone
matrix and the peripheral clear zone of the osteoclast. The
acidification of this confined space facilitates the dissolution of
calcium phosphate from bone and is the optimal pH for the
activity of lysosomal hydrolases. Bone matrix is thus removed,
and the products of bone resorption are taken up into the
cytoplasm of the osteoclast, probably digested further, and
transferred into capillaries. The chemical equation shown in the
figure refers to the action of carbonic anhydrase II, described in
the text. (Reproduced, with permission, from Junqueira LC,
Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill,
2003.)
Coordination of Resorption and

Formation
Phase
Signal
from osteoblasts
Stimulation of osteoblastic precursor cells to
become osteoclasts
Process takes 10 days
Coordination of Resorption and

Formation
Phase
II
Osteoclast
resorb bone creating cavity

Macrophages clean up
Phase
III
New bone laid down by osteoblasts

Takes 3 months
Pathways of differentiation of
osteoclasts and osteoblasts
Hormonal Influence
Vitamin
D
Parathyroid Hormone
Calcitonin
Estrogen
Androgen
Vitamin D
Osteoblast
have receptors for (1,25-(OH)2-D)

Increases activity of both osteoblasts and
osteoclasts
Increases osteocytic osteolysis (remodeling)
Increases mineralization through increased intestinal
calcium absorption
Feedback action of (1,25-(OH)2-D) represses gene
for PTH synthesis
Parathyroid Hormone
Accelerates removal of calcium from bone to increase Ca

levels in blood
PTH receptors present on both osteoblasts and osteoclasts
Osteoblasts respond to PTH by
Change of shape and cytoskeletal arrangement

Inhibition of collagen synthesis
Stimulation of IL-6, macrophage colony-stimulating factor secretion
Chronic stimulation of the PTH causes hypercalcemia and

leads to resorptive effects of PTH on bone
Parathyroid Hormone (PTH)

Single
most important hormone in the control of

blood [Ca2+].
Stimulated by decreased blood [Ca2+].
Stimulates
osteoclasts to reabsorb bone.

Stimulates kidneys to reabsorb Ca2+ from glomerular
filtrate, and inhibit reabsorption of P043-.
Promotes formation of 1,25 vitamin D3.
Many cancers secrete PTH-related protein that
interacts with PTH receptors.
Produce hypercalcemia.
Calcitonin
C
cells of thyroid gland secrete calcitonin

Straight chain peptide - 32 aa
Synthesized from a large preprohormone
Rise in plasma calcium is major stimulus of
calcitonin secretion
Plasma concentration is 10-20 pg/ml and half
life is 5 min
Actions of Calcitonin
Osteoclasts
are target cells for calcitonin

Major effect of calcitonin is rapid fall of plasma
calcium concentration caused by inhibition of
bone resorption
Magnitude of decrease is proportional to the
baseline rate of bone turnover
Calcitonin
Works with PTH and 1,25 vitamin D3 to
regulate blood [Ca2+].
Stimulated by increased plasma [Ca2+].
Inhibits the activity of osteoclasts.
Stimulates urinary excretion of Ca2+ and P043by inhibiting reabsorption.
Physiological significance in adults is
questionable.
1,25 Vitamin D3
Pre-vitamin D3 is synthesized in the skin when
exposed to mid-ultraviolet waves.
Pre-vitamin D3 isomerized to vitamin D3 (cholecalciferol).
Cholecalciferol is hydroxylated in liver to form 25

hydroxycholecalciferol.
In proximal convoluted tubule is hydroxylated to
1,25 dihydroxycholecalciferol (active vitamin D 3).
Stimulated by PTH.

Production of
1,25 dihydroxyvitamin D3
Insert fig. 19.20

1,25 dihydroxyvitamin
D3
(continued)
Directly stimulates intestinal absorption of Ca 2+ and

P043-.
When Ca2+ intake is inadequate, directly stimulates
bone reabsorption.
Stimulates reabsorption of Ca2+ and P043- by the
kidney.
Simultaneously raising Ca2+ and P043- results in increased
tendency of these 2 ions to precipitate as hydroxyapatite
crystals.
Stimulated by PTH.
Negative Feedback
Control
Insert fig. 19.23

Other systemic
hormones
Estrogens
Increase bone remodeling
Androgens
Increase bone formation

Other systemic
hormones
Growth hormone
Increases bone remodeling
Glucocorticoids
Inhibit bone formation
Thyroid hormones
Increase bone resorption
Increase bone formation

Hormonal Mechanism
Figure 6.12
Hormonal Control of Blood Ca
Rising blood
Ca2+ levels
Imb
ala
nce
Calcium homeostasis of blood: 911 mg/100 ml

Imb
ala
nce
Figure 6.11
Thyroid
gland
Rising blood
Ca2+ levels
Imb
ala
nce

Imb
ala
nce
Figure 6.11

PTH;
calcitonin
secreted
Thyroid
gland
Rising blood
Ca2+ levels
Imb
ala
nce

Imb
ala
nce
Figure 6.11

PTH;
calcitonin
secreted
Calcitonin
stimulates
calcium salt
deposit
in bone
Thyroid
gland
Rising blood
Ca2+ levels
Imb
ala
nce

Imb
ala
nce
Figure 6.11

PTH;
calcitonin
secreted
Calcitonin
stimulates
calcium salt
deposit
in bone
Thyroid
gland
Rising blood
Ca2+ levels
Figure 6.11
Imb
ala
nce

Imb
a la
nce
Falling blood
Ca2+ levels
Figure 6.11

Imb
ala
nce

Imb
a la
nce
Falling blood
Ca2+ levels
Thyroid
gland
Parathyroid
glands
Parathyroid
glands release
parathyroid
hormone (PTH)
Figure 6.11

Imb
ala
nce

Imb
a la
nce
Falling blood
Ca2+ levels
Thyroid
gland
Parathyroid
glands
Parathyroid
glands release
parathyroid
hormone (PTH)
PTH
Figure 6.11

Imb
ala
nce

Imb
a la
nce
Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone
matrix and release
Ca2+ into blood
Parathyroid
glands
Parathyroid
glands release
parathyroid
hormone (PTH)
PTH
Figure 6.11

Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone
matrix and release
Ca2+ into blood
Parathyroid
glands
Parathyroid
glands release
parathyroid
hormone (PTH)
PTH
Figure 6.11

PTH;
calcitonin
secreted
Calcitonin
stimulates
calcium salt
deposit
in bone
Thyroid
gland
Imb
Rising blood
Ca2+ levels
ala
nce

Imb
a la
nc
e
Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone
matrix and release
Ca2+ into blood
Parathyroid
glands
PTH
Parathyroid
glands release
parathyroid
hormone (PTH)
Figure 6.11
Bone Growth and Calcium Metabolism
Epiphyseal plate new bone growth site

Chondrocytes, osteoblasts & calcification build bone
Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Calcium Homeostasis
Bone is major storage site for calcium
The level of calcium in the blood depends upon
movement of calcium into or out of bone.
Calcium enters bone when osteoblasts create new
bone; calcium leaves bone when osteoclasts break
down bone
Two hormones control blood calcium levelsparathyroid hormone and calcitonin.
6-56
Calcium Homeostasis
6-57
Bone Growth and Calcium Metabolism
Figure 23-19: Bone growth at the epiphyseal plate

Calcium Metabolism:
Maintain [plasma]: from diet, from bone "storage",

recycled
Key roles: muscle contraction, bone support, cell
signaling
PLAY
Animation: Fluids & Electrolytes: Electrolyte Homeostasis
Calcium Metabolism:
Figure 23-20: Calciumbalanceinthebody

Control of Calcium Balance & Metabolism

Parathyroid H
Calcitrol
Vitamin D
Sun/diet
Calcitonin
Thyroid
C-cells
(Phosphate balance)
Figure 23-23: Endocrine control of calcium balance
Osteoporosis:
Disease of Bone Growth & Calcium Metabolism
Bone reabsorption
exceeds deposition
Osteoclasts mobilize
Ca++ to plasma
Factors: inadequate
Ca++ intake, genes,
hormones, smoking
Figure 23-21: Osteoclasts are responsible for bone resorption
PTH, Calcium
& Phosphate
What is cartilage?
Skeletal tissue--maintains certain shape and form

Very resilient (bouncy or rubbery), mostly water
Grows fast--forms embryonic skeleton
Kinds of cartilage
Hyaline cartilage--most common, found in joints

Elastic cartilage--epiglottis, ear
Fibrocartilage--annular fibrosis of intervertebral disk,
menisci of knee
cartilage

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Bone is a

Cells of Bone Tissue

Bone contains both organic and inorganic material.

The inorganic or mineral component is mainly crystalline

Bone is a dynamic structure that undergoes

Chemical Composition of Bone

Organic components of bone

Chemical Composition of Bone

Osteoblasts are bone

Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings

Chemical Composition of Bone

Chemical Composition of Bone:

Sixty-five percent of bone by

Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings

bone matrix from sites where it is

Chemistry of the bone

Direct formation of fibers

Mineralization of the bone

occurs by extracellular deposition

of calcium and phosphate ions in

exist to both initiate and inhibit

Bone remodeling process

Bone remodeling process

Bone remodeling cycle (1)

Non Commercial Use Only

Bone remodeling cycle (2)

Bone remodeling cycle (3)

Non Commercial Use Only

Bone Deposition and

Bone Deposition and Resorption

Bone resorption occurs when an osteoclast attaches to the

Protein matrix digested by cathepsin K.

Non Commercial Use Only

Bone Deposition and Resorption

Non Commercial Use Only

Non Commercial Use Only

Figure 4812. Schematic illustration of some aspects of the

Coordination of Resorption and

Coordination of Resorption and

resorb bone creating cavity

New bone laid down by osteoblasts

have receptors for (1,25-(OH)2-D)

Accelerates removal of calcium from bone to increase Ca

Change of shape and cytoskeletal arrangement

Chronic stimulation of the PTH causes hypercalcemia and

Parathyroid Hormone (PTH)

most important hormone in the control of

Stimulated by decreased blood [Ca2+].

osteoclasts to reabsorb bone.

cells of thyroid gland secrete calcitonin

are target cells for calcitonin

Cholecalciferol is hydroxylated in liver to form 25

Non Commercial Use Only

Insert fig. 19.20

Non Commercial Use Only

Directly stimulates intestinal absorption of Ca 2+ and

Insert fig. 19.23

Non Commercial Use Only

Non Commercial Use Only

Non Commercial Use Only

Hormonal Control of Blood Ca

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Hormonal Control of Blood Ca