Download MBBS Extracelular Matrix 3 Lecture PPT

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DR. S. SHEKHAR

ASSOC. PROFESSOR

DEPT. OF BIOCHEMISTRY

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PROTEOGLYCAN

? A proteoglycans consists of a core protein bound covalently

to GAGs, and these units form large complexes with other

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components of the extracellular matrix, such as hyaluronic
acid or collagen.

? GAGs consist of repeating disaccharide subunits.
? Proteins linked covalently to glycosaminoglycans (GAGs).

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Carbohydrates make up about 95% of its weight.

? Proteins bound covalently to GAGs are called core proteins.
? Many have been classified; they vary in tissue of origin,

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function, core protein types.

? Examples include aggrecans, syndecan, betaglycan,

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serglycan


PROTEOGLYCAN

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? The highly negatively charged

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sulfated sugars on the
proteoglycan "bristles" recruit
sodium and water to generate
a viscous but compressible
matrix.

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? They have diverse role in

regulating connective tissue
structure and permeability (ie

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regulates

movement

of

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molecules through matrix).


? They also serve as reservoir of growth factors (eg

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FGF & HGF), they act as modulators of cell growth
and differentiation.

? In joint cartilage they also provide layer of lubrication

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between bony surfaces.

? Some are integral part of cell membrane & have roles

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in cell proliferation, migration and adhesion

? Highly hydrated compressible gels that confer

resistance to compressive forces.

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Glycoaminoglycans

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? Unbranched polysaccharide chains composed of

repeating dissacharide units.

? Negatively charged under physiological conditions (due

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to the occurrence of sulfate and uronic acid groups)

? Disaccharide subunits are:
1. Uronic acid

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D-glucuronic acid or
L-iduronic acid
2. Aminosugar
N-acetyl glucosamine (GlcNAc) or
N-acetyl galactosamin (GalNAc)

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Glycoaminoglycans

? Amino sugars and uronic acids are

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the most common building blocks
of the glycosaminoglycans.

? amino sugars -OH at C-2 is

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replaced by an amino group. This
amino group is most often
acetylated and sometimes sulfated.

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? uronic acids C-6 of the hexose is

oxidized to a carboxyl group.

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Linkage of GAGs to protein core by specific

trisaccharide linker

GALACTOSE

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GALACTOSE

XYLOSE
Types of GAGs

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Seven types of GAGs
1. Hyaluronan
2. Chondroitin sulfate
3. Dermatan sulfate

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4. Heparin
5. Heparan sulfate
6. Keratan sulfate I
7. Keratan sulfate II

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1. Hyaluronan

? Made up of Unbranched,

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repeating units of GlcUA
and GlcNAc

? It tends to have enormous

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carbohydrate chain

? Not covalently attached to

a core protein

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? The carbohydrates are not sulfated

? Especially high in concentration in highly hydrated
tissues such as skin and umbilical cord, and in bone,

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cartilage, joints (synovial fluid) and in vitreous humor in
the eye, as well as in embryonic tissues
Hyaluronan

? permitting cell migration during morphogenesis

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? Important in wound healing
? Its ability to attract water into the ECM triggers

loosening of the matrix

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? The high concentrations of hyaluronic acid together

with chondroitin sulfates present in cartilage
contribute to its compressibility

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? Hyaluronidase an enzyme secreted by some bacteria

helps with their invasion of tissues

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2. Chondroitin sulfate

? Repeating unit of GlcUA

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and GalNAc

? Attached to a core protein

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through xyl-serine

? Sulfated carbohydrates

? Tends to have shorter polymers

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Chondroitin sulfate

? They are located at sites of calcification in

endochondral bone and are a major component

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of cartilage.

? Provides tensile strength to cartilage, tendons,

ligaments and walls of aorta

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? Thought to act as signaling molecules in the

prevention of the repair of nerve endings after
injury.

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3.Dermatan sulfate

? Made up of repeating

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IdUA and GalNAc.

? May also contain GlcUA
? Attached to a core protein

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through xyl-serine

? Widely distributed troughout the body.

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Contributes to the pliability of the skin

? Evidence suggests it may play a part in blood

coagulation, wound repair and resistance to

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infection


Keratan Sulfate (KS) I and II

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? Repeating units of Gal and

GlcNAc

? KS I is attached to core

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protein through GlcNAc-Asp

? KS II is attached through

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GalNAc-Thr

? Present mainly in cornea,

cartilage, bone

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? In the eye, they lie between collagen fibrils and play a

critical role in corneal transparency

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Heparin

? Repeating units of GlcN (mostly

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sulfated but sometimes acetylated)
and either of the gluconic acids
mostly iduronic acid

? Heparin is linked to its core protein

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(mostly glycine and serine) through
a bond with serine

? Heparin is mostly intracellular

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unlike rest of GAGs-in mast cells

? Involved in anticoagulation by binding factor factor IX, XI

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and Plasma antithrombin III

? Binds lipoprotein lipase in endothelial cell walls and puts

them into circulation

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Heparan sulfate

? Made up of GlcN and

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uronic acid predominantly
glucoronic acid

? Attached to its core

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protein through xyl-serine

? Mainly extracellular

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? Associated with the plasma membrane of cells, may
act as receptors and may also participate in the mediation of
the cell growth and cell - cell communication
? This proteoglycan is also found in the basement membrane of
the kidney along with type IV collagen and laminin where it

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plays a major role in determining the charge selectiveness of
glomerular filtration.
Synthesis of proteoglycans

? Starts with core protein synthesis from ribosomes on

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the RER

? The addition of GAGs takes place in the Golgi

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Apparatus

? The addtions of the GAGs to their core protein is of

three types:

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1. O-glycosidic linkage between xylose and serine

(xyl-gal-gal-glcua)

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2. O-glycosidic linkage between GalNAc and serine

eg in Keratan sulfate II

3. N-glycosylsamine bond between GlcNAc and

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asparagine
Elongation

Further modifications

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? The units in the

? Epimerization

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of

saccharide chains are

glucoronic

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acid

to

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elongated in alternating

iduronic acid catalysed

acidic/amino

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sugars,

by epimerases

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donated from UDP
derivatives

through

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specific

glycosyl

? Sulfation of the amine

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transferases

sugars are catalysed by
sulfo-transferases

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Function of Proteoglycans

? organize water molecules
- resistent to compression
- return to original shape

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- repel negative molecules
? occupy space between cells and collagen
? high viscosity - lubricating fluid in the joints
? specific binding to other macromolecules
Function of Proteoglycans

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? link to collagen fibers - form network - in bone

combine with calcium salts (calcium
carbonate, hydroxyapatite)

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? cell migration and adhesion - passageways

between cells

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? anchoring cells to matrix fibers
Degradation of GAGs and Inborn Errors of

Metabolism

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? Inborn

error

of

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? GAGs are degraded

metabolism affecting

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by

specific

any of these enzymes

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lysosomal enzymes

results in accumulation

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including exo and

of GAGs in lysosome

endoglycosidases,

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mucupolysaccharidoses

sulfatases

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Eg.

Hurler's

and

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Hunter's syndrome

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Causation of a mucopolysaccharidosis

Mutation(s) in a gene encoding a lysosomal hydrolase

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involved in the degradation of one or more GAGs

Defective lysosomal hydrolase

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Accumulation of substrate in various tissues,
including liver, spleen, bone, skin, and central nervous
system
Mucopolysaccharidoses (MPSs)

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? Autosomal recessive (exception Hunter disease, X-

linked recessive

? Hurler and Hunter syndromes (most widely studied)

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? Chronic and progressive and affect multiple organs.
Many patients exhibit
? Organomegaly (eg, hepato- and splenomegaly)
? Severe abnormalities in the development of cartilage and

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bone

? Abnormal facial appearance
? Mental retardation.
? In addition, defects in hearing, vision and the

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cardiovascular system may be present.
MPS I (Hurler)

? Deficiency of -L-iduronidase

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? Is a severe, progressive disorder with multiple

organ and tissue involvement that results in

premature death, usually by 10 years of age

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Clinical features:
? Corneal clouding ? Dysostosis multiplex
? Hepatosplenomegal y ? Mental retardation
? Cardiomyopathy ? Coarse facial

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features

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Intraoral picture showing

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Corneal clouding

decayed

teeth

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and

macroglossia

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Short stature

skeletal dysplasia

Large tongue

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Joint stiffness

known as dysostosis

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multiplex

Hurler Disease
BIOCHEMISTRY OF BONE

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? Bone is made up of the

Cellular Part

matrix and the cells

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i. Osteoblast

Matrix

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ii. Osteoclast

? Bone matrix is made up

iii. Osteocytes

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of organic and inorganic

matter.

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iv. Osteoprogenitor

? Organic matter makes up

about 20-40%

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Inorganic matter - 60%
Water makes about 10%
Matrix

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Organic

Inorganic

Collagen Type I - 90-95% Hydroxyapatite ? Ca10(PO4 )6 (OH)2

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Collagen Type V

Octacalcium phosphate -

Ca8H2 (PO4 )6 .5H2O

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Osteonectin

Brusite ? CaHPO4 .2H2O

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Osteocalcin

Amorphouse calcium

Proteoglycans (Biglycan,

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phosphates ? Ca9 (PO4 )6

Decorin)

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Magnesium
Fluoride
Sodium
Metabolism

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? Bone is a dynamic structure
? Undergoes remodelling in form of resorption and

deposition of new bones

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? Remodelling is under the influence of hormones

and physical demands (eg weight bearing)

? Resorption of bones is performed by osteoclast

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? Deposition of bones is performed by osteoblast
? Approximately 4% of compact bone and 20% of

trabecular gets renewed annually
Osteoblast and bone deposition

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Osteocalcin

? Osteoblast

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are

Protein with carboxylated

mononucleated

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glutamate with help of Vit

K.

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? Descendants

of

mesenchymal marrow

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Acts as a dock for Ca2+

cells

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which finally reacts with

phosphates

to

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form

? Lays down bone matrix

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hydroxyapatite

(osteoid) - collagen,

osteocalcin, osteonectin.

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Osteonectin

Collagen type I and V

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osteoid protein that makes

contact collagen I and

hydroxyapatite

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Schematic illustration of the major cells present in the membranous bone.

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Osteoblasts are synthesizing type I collagen, which forms a matrix that traps
cells. As this occurs, osteoblasts gradually differentiate to become osteocytes.
? Osteoblast synthesize

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most of the proteins found in

bones as well as growth factors and cytokines

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needed for mineralization.

? Osteoblast synthesize the new bone matrix called

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osteoid and cause its mineralization.

? They contain alkaline phosphatase in their apical

surface which releases phosphates from organic

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phosphates.

? Bone proteins such as bone sialoproteins (e.g.

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tyrosin rich acid matrix proteins or TRAMP) and

osteopontin bind calcium through their structural

motiffs rich in aspartate and glutamate.

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? These proteins provide the initial side of nucleation

for mineralization which is facilitated by localized

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high calcium and phosphate concentration

? Ionic product of Ca+2 and PO -3

4 of 70 or more

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(average = 40) stimulate mineralization.

? Osteoblast

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subsequently

differentiate

into

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osteocytes to maintain matrix.
OSTEOCLAST AND BONE RESORPTION

? Multinucleated cells, interspersed between osteoblast

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? Cause resorption of bones
? These cells have ruffled border in their apical membrane

which is in contact with bone matrix.

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? Protons and lysosomal enzymes such as acid proteinase

released into this area create a micro environment of low

pH (below 4.0)

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? The hydroxyapatite crystal solubilizes in this environment

and bone proteins in matrix are degraded leading to bone

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resorption.

? Products of the bone resorption are taken up in the

cytoplasm of osteoclasts for further digestion and

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transferred into capillaries


? Osteoclast seals off matrix

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to be resorbed

? H/K ATPase pump- pumps H+ into the matrix (pH=4)

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increasing the solubility of hydroxyapatite

? Lysosomal acid hydrolases

(acid

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phosphatases,

collagenases,

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sulfatases,

Cathepsin K) exocytosed
into the matrix to hydrolyse
the matrix

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? HCO3 - is extruded out of

the cell to maintain
intracellular pH

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Regulation of bone metabolism

? Many factors are involved in the regulation of

bone metabolism.

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? Glucocorticoids ? inhibition of bone formation.
? Growth hormone (GH) ? stimulation of bone

formation through somatomedins (growth factors

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IGF-1 and IGF-2).

? Insulin ? stimulation of synthetic activity of

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osteoblasts.

? Thyroid hormones ? stimulation of osteoclasts,

activation of bone remodelation.

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Regulation of bone metabolism

? Estrogens ? inhibition of bone resorption

(inhibition of osteoclastic activity through

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specific local factors).

? Catecholamines ? antagonists of calcitonin.
? Prostaglandins ? different classes of

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prostaglandins have different effect, which is

dependent on concentration (10-9 ? 10-7 mol/l

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stimulates synthesei of collagen, 10-6 inhibits

collagen synthesis.
Calcium homeostasis

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A. Parathyroid hormone (parathyroid)
? Released by low plasma calcium.
? Stimulates bone resorption.
? Prevents calcium excretion by kidneys.
? Stimulates calcitriol synthesis.

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B. Calcitriol (1,25-diOH-Vit. D)
? 25-hydroxylation in liver
? 1-hydroxylation in kidney
? Stimulates bone resorption.
? Stimulates intestinal calcium absorption

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Calcium homeostasis

C. Calcitonin (thyroid)
? Is released by high plasma calcium.
? Acts on bone osteoclasts to reduce bone

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resorption.

? Net result of its action is a decline in plasma

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calcium & phosphate.


CARTILAGE

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1. Hyaline
- Flexible and resilient
? Chondrocytes appear

spherical

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? Lacuna ? cavity in matrix

holding chondrocyte

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? Collagen the only fiber


2. Elastic

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3. Fibrous

- highly- bendable

-resists compression and

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- Matrix with elastin as

tension

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well as collagen fibers

- Rows of thick collagen

- Epiglottis, larynx and

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fibers alternating with

outer ear

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rows of chondrocytes

(in matrix)

- Knee menisci and

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annunulus fibrosis of

intervertebral discs

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The Principal Proteins Found in Cartilage

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Schematic representation of the molecular organization in the cartilage

matrix.

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Link proteins noncovalently bind the core protein (red) of proteoglycans
to the linear hyaluronic acid molecules (gray). The chondroitin sulfate
side chains of the proteoglycan bind to the collagen fibrils, forming a
cross-linked matrix
CHONDROCYTES

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? Progenitor cells arise in marrow
? Progenitor cells differentiate into chondroblast
? Chondroblast-secrete chondrin the primary substance in

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cartilage for building and repairing cartilage

? When chondroblast get completely surrounded by matrix-

chondrocytes

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? Chondrocytes in gaps called lacunae
? Functions to produce and maintain the extracellular

matrix

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? CHONDRONECTIN is involved in the attachment of type II

collagen to chondrocytes (the cells in cartilage)

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? Cartilage is an avascular tissue and obtains most of its

nutrients from synovial fluid.

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? It exhibits slow but continuous turnover.
? Various proteases (eg, collagenases and stromelysin)

synthesized by chondrocytes can degrade collagen
and the other proteins found in cartilage.

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? Interleukin-1 (IL-1) and tumor necrosis factor

(TNF) stimulate the production of such proteases.

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? Whereas transforming growth factor (TGF) and

insulin-like growth factor 1 (IGF-I) generally exert an
anabolic influence on the cartilage.

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Cartilage Matrix

AGGRECAN

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Composition
? Collagen ?Type II (main matrix

collagen) and I

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? Elastin and fibrous cartilages

contain elastin and type II
collagen respectively

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? Proteoglycans-
Aggrecan is the main one.
Others include chondronectin.
Attaches to Collagen type II
Clinical Correlation-Bone and Cartilage

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Osteogenesis imperfecta
? Mutations in gene encoding type I collagen
? Leads to increased bone fragility
? scleras are often abnormally thin and translucent and may

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appear blue

? Severe forms-babies born with multiple fractures-mostly

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fatal

? Eight types (I-VIII) of this condition have been

recognized.

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? Types I to IV are caused by mutations in the COL1A1 or

COL1A2 genes or both

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? Mutation causes replacement of glycine by another

bulkier amino acid, affecting formation of the triple helix.
Osteogenesis imperfecta

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? These mutations result in decreased expression of

collagen or in structurally abnormal pro chains that
assemble into abnormal fibrils, weakening the overall
structure of bone

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? When one abnormal chain is present, it may interact

with two normal chains, but folding may be prevented,
resulting in enzymatic degradation of all of the chains.

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This is called "procollagen suicide

? Types V to VIII are less common and are caused by

mutations in the genes for proteins involved in bone

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mineralization other than collagen
BRITTLE BONE DISEASE

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Osteopetrosis (marble bone disease)

? Decreased ability to resorb bones
? Increased density of the bones

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? Due to mutation in gene encoding carbonic anhydrase

II.

? Deficiency of CA II in osteoclat prevent normal bone

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resorption, and osteopetrosis results.

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BONE MODELLING AND REMODELLING

? MODELLING- during growth, skeleton increases in

size by apposition of new bone tissue on outer surface

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of cortex.

? REMODELLING- It is a cellular process of bone

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activity by which both cortical and cancellous bone are

maintained.

? Bone remodelling has two main functions-

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1. To repair micro damage within skeleton to maintain

skeletal strength.

2. To supply calcium to maintain serum calcium levels

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? OSTEOPOROSIS results from bone loss due to age

related changes in bone remodelling as well as extrinsic

and intrinsic factors that exagerate this process.

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Osteoporosis

? Generalized progressive reduction in bone tissue mass per

unit volume (densimetric studies) causing skeletal

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weakness.

? weak bones prone to fracture
? Resorption>deposition

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? Primary- age related. Women>men
1. Decrease in estrogen and androgen concentrations
2. Reduced physical activity
3. Insufficient vitamin D and calcium intake
4. Reduced UV exposure, resulting in lower endogenous

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production of vitamin D

5. Reduced renal function secondary to diabetes,

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arteriosclerosis, or analgesics abuse, resulting in

insufficient 1-hydroxylation necessary to activate vitamin

D

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Dual-energy X-ray

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absorptiometry (DEXA)

? Gold standard method

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to determine bone
mineral density.
Advantages

1. Rapid and non invasive

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technique

2. Radiation exposure is

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minimal

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Dwarfism - Achondroplasia
Achondroplasia

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? Affected individuals have short limbs, normal

trunk size, macrocephaly, and a variety of
other skeletal abnormalities.

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? often inherited as an autosomal dominant trait,

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Rickets

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Osteomalacia

Lack of vitamin D in

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Lack of vitamin D in

children

adults

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1. Bones of children are 1. Bones are inadequately

inadequately

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mineralized

causing

mineralized

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causing

softened,

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weakened

softened,

weakened

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bones

bones

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2. Main symptom is pain

2. Bowed

legs

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and

when weight is put on

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deformities of the

the affected bone

pelvis, skull, and rib

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cage are common

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?