EXTRACELLULAR
MATRIX 3
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DR. S. SHEKHARASSOC. 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 hyaluronicacid 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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serglycanPROTEOGLYCAN
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? The highly negatively charged
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sulfated sugars on theproteoglycan "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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regulatesmovement
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 ofrepeating 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 orL-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 isoxidized to a carboxyl group.
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Linkage of GAGs to protein core by specifictrisaccharide 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. Heparin5. 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 GlcUAand 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 inthe 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 togetherwith chondroitin sulfates present in cartilage
contribute to its compressibility
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? Hyaluronidase an enzyme secreted by some bacteriahelps 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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infectionKeratan Sulfate (KS) I and II
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? Repeating units of Gal andGlcNAc
? 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, mayact 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 ofglomerular 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 serineeg 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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ofsaccharide chains are
glucoronic
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acid
to
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elongated in alternatingiduronic acid catalysed
acidic/amino
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sugars,
by epimerases
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donated from UDPderivatives
through
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specificglycosyl
? 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 fibersDegradation of GAGs and Inborn Errors of
Metabolism
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? Inbornerror
of
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? GAGs are degraded
metabolism affecting
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byspecific
any of these enzymes
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lysosomal enzymes
results in accumulation
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including exo andof 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 multipleorgan 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 cloudingdecayed
teeth
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and
macroglossia
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Short statureskeletal dysplasia
Large tongue
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Joint stiffness
known as dysostosis
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multiplexHurler Disease
BIOCHEMISTRY OF BONE
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? Bone is made up of theCellular 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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OrganicInorganic
Collagen Type I - 90-95% Hydroxyapatite ? Ca10(PO4 )6 (OH)2
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Collagen Type VOctacalcium phosphate -
Ca8H2 (PO4 )6 .5H2O
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Osteonectin
Brusite ? CaHPO4 .2H2O
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OsteocalcinAmorphouse calcium
Proteoglycans (Biglycan,
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phosphates ? Ca9 (PO4 )6
Decorin)
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MagnesiumFluoride
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 hormonesand 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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areProtein with carboxylated
mononucleated
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glutamate with help of Vit
K.
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? Descendantsof
mesenchymal marrow
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Acts as a dock for Ca2+
cells
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which finally reacts withphosphates
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 makescontact 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) andosteopontin 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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subsequentlydifferentiate
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 proteinasereleased 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 inhibitscollagen 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 homeostasisC. 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 fiber2. 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 proteoglycansto 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) andinsulin-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 cartilagescontain 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 anotherbulkier amino acid, affecting formation of the triple helix.
Osteogenesis imperfecta
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? These mutations result in decreased expression ofcollagen 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 collagenBRITTLE 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 anhydraseII.
? 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 aremaintained.
? Bone remodelling has two main functions-
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1. To repair micro damage within skeleton to maintainskeletal strength.
2. To supply calcium to maintain serum calcium levels
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? OSTEOPOROSIS results from bone loss due to agerelated 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>men1. 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 ininsufficient 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 bonemineral density.
Advantages
1. Rapid and non invasive
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technique
2. Radiation exposure is
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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 inchildren
adults
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1. Bones of children are 1. Bones are inadequately
inadequately
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mineralizedcausing
mineralized
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causing
softened,
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weakenedsoftened,
weakened
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bones
bones
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2. Main symptom is pain2. Bowed
legs
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and
when weight is put on
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deformities of thethe affected bone
pelvis, skull, and rib
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cage are common
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?
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