Transcript BIOCHEMISTRY OF CARTILAGE

BIOCHEMISTRY OF CARTILAGE
DEFINITION
Specialized form of connective tissue
with firm consistency of extra-cellular matrix, allow
the tissue to bear mechanical stresses without
permanent distortion and Support soft tissues .
Sliding areas for joints to facilitate movement
Provides a model for the formation of most of
the bones in the body.
TYPES OF CARTILAGES
HUMAN BODY HAS THREE TYPES OF CARTILAGES
Hyaline Cartilage
articular cartilage
larynx
rib and costal cartilage
nasal septum
Elastic Cartilage
epiglottis
Fibrocartilage
Intervertebral disk
meniscus
The extracellular space in animal tissues is filled
with a gel-like material, the extracellular
matrix, also called ground substance,
which holds the cells of a tissue together and
provides a porous pathway for the diffusion of
nutrients and oxygen to individual cells.
Epithelial cells
extracellular
matrix
Underlying
cells
The extracellular matrix is composed of an
interlocking meshwork of
heteropolysaccharides and fibrous
proteins.
• Heteropolysaccharides in the body
are the glycosaminoglycans (GAGs).
These molecules are long
unbranched polysaccharides
containing a repeating disaccharide
unit.
• The disaccharide units contain either
of two modified sugars, called amino
sugars N-acetylgalactosamine
(GalNAc) or N-acetylglucosamine
(GlcNAc),
• and an acidic sugar uronic acid such
as glucuronic acid or iduronic acid.
• GAGs are highly negatively charged
molecules, with extended
conformation that imparts high
viscosity to the solution.
• GAGs are located primarily on the
surface of cells or in the
extracellular matrix (ECM).
Structure of Glycosaminoglycans
• GAGs in the body are linked to core
proteins ( except hyaluronic acid),
forming proteoglycans (also called
mucopolysaccharides).
CHONDROCYTES
Cells that synthesize and secrete Extracellular
Matrix
The cells are located in matrix cavity called
Lacunae
CHONDROCYTES
EXTRACELLULAR MATRIX (25%)
Fibers
Collagen (II)
Elastin
fibrillin
Ground substances
Proteoglycan (Aggregan)
Glycoprotein
The chains are linear (unbranched)
They are linked to the protein core via a serine or
threonine (O-linked) (except HA) forming
Proteoglycan.
Negative charge due to OH, COOH, and SO4, PG
are hydrophillic and act as polyanion attract +ions
(K and Na)
Highly solvated and viscous.
FIBRES CREATES A FRAMEWORK THAT HOUSES THE OTHER COMPONENTS OF
CARTILAGE
COLLAGEN (15%)
Majority (90-98%) is
Type II collagen.
Provides cartilage
with its tensile
strength
Compressive
properties
Fluid flow
GROUNDSUBSTANCE
Highly hydrated complex of mixture of
proteoglycans and glycoproteins
Proteoglycans are linear polysaccharides of
repeating disaccharide units composed of
hexosamine & uronic acid
Glucosamine/Galactosamine
Glucoronic acid/Iduronic acid
Linkage
• The linkage of GAGs to the protein
core involves a specific trisaccharide
composed of two galactose residues
and a xylose residue (Gal-Gal-Xyl-OCH2-protein).
PROTEOGLYCAN: PROTEIN WITH BOUND SIDE CHAINS
(GLYCOSAMINOGLYCANS
HETERO POLYSACCHARIDES (GAG) OF THE
EXTRA-CELLULAR MATRIX
Hyaluronic acid - glassy and translucent
lubricants in joints, cartilage, and tendons
hyaluronidase in pathogenic bacteria and
sperm
Hyaluronic acid (D-glucuronate + GlcNAc)
2) Chondroitin sulfate(D-glucuronate + GalNAc sulfate)
It is the most abundant GAG.
cartilage, tendon, ligament, and walls of the aorta
Dermatan sulfate (L-iduronate + GlcNAc sulfate)
Occurence : skin, blood vessels, heart valves
Heparin - natural anticoagulant made in mast cells
bind antithrombin, then bind and inhibit thrombin
Keratan sulfate ( Gal + GlcNAc sulfate)
Occurence : cornea, bone, cartilage ;
Keratan sulfates are often aggregated with chondroitin
sulfates.
Structure of proteoglycans
The GAGs extend perpendicular from the core
protein in a bottlebrush- like structure.
The linkage of GAGs to the protein core
involves a specific trisaccharide .The protein
cores of proteoglycans are rich in Ser and Thr
residues which allows multiple GAG
attachment.
Much of the compressive strength of
cartilage is derived from the
glycosaminoglycan molecules in the
extracellular matrix.
These molecules have abundant
carboxyl and sulfate groups that are
negatively charged under physiologic
conditions
PROTEOGLYCAN FUNCTIONS
Modulation of cell growth processes
Binding of growth factor proteins by proteoglycans
in the glycocalyx provides a reservoir of growth
factors at the cell surface.
Cushioning in joints
Cartilage matrix proteoglycans absorb large
amounts of water. During joint movement,
cartilage is compressed, expelling water!
Some Functions of Glycosaminoglycans and
Proteoglycans
•
Act as structural components of the ECM Have specific
interactions with collagen, elastin, fibronectin, laminin,
and other proteins such as growth factors
• As polyanions, bind polycations and cations
• Contribute to the characteristic turgor of various
tissues
• Act as sieves in the ECM Facilitate cell migration (HA)
• Have role in compressibility of cartilage in weightbearing (HA, CS)
• Play role in corneal transparency (KS I and DS)
• Have structural role in sclera (DS)
• Act as anticoagulant (heparin)
• Are components of plasma membranes, where they
may act as receptors and participate in cell adhesion
and cell-cell interactions (eg, HS)
• Determine charge-selectiveness of renal glomerulus
(HS)
• Are components of synaptic and other vesicles (eg, HS)
When glycosaminoglycans are lost from the
cartilage matrix, as occurs in trauma or
osteoarthritis, the mechanical stiffness of
the tissue is dramatically reduced, and the
functional integrity of the cartilage is
compromised.
.
Maintaining and restoring
glycosaminoglycans in adequate
concentrations in the extracellular matrix are
therefore important targets for therapeutic
interventions.
Understanding the loss and replenishment
of glycosaminoglycans is potentially
important in determining the correct
diagnosis early, monitoring the disease, and
selecting treatments