❑ Living tissues are not just accumulations of tightly

packed cells

❑ Much of a tissue’s volume is made up of extracellular

space

❑ ‘extra’ - meaning ‘outside’ or ‘beyond’

❑ This void is filled with a complex meshwork →

extracellular matrix (ECM)
Uniqueness of Extracellular Matrix

❑ Rather than being inert filler material, the

extracellular matrix is a dynamic, physiologically
active component of all living tissues

❑ Extracellular matrix largely determines how a

tissue looks and functions

❑ Variations in types and number of molecules in the

extracellular matrix of connective tissue → incredible
diversity of tissues and organs in the human body
Example for Uniqueness of Extracellular Matrix

thick and highly

mineralized, providing a consists of a water-rich,
tissue that is hard, transparent, flexible gel -
inflexible and opaque - ideal for transmitting light
just the thing for into the eyeball
building a skeleton
Extracellular
Matrix
(ECM)

Credit: Vshivkova/Shutterstock.com
 What is Extracellular Matrix (ECM)?

➢ three-dimensional network of extracellular

macromolecules that provide structural and
biochemical support of surrounding cells

➢ constitutes the non-cellular component of all tissues

and organs

➢ actually plays an important part in the development,

differentiation, and maintenance of the tissue and
organ
Components of Extracellular Matrix (ECM)
Present between various
Interstitial matrix cells – in intercellular spaces
& surround the cells
Animal ECM
Basement sheet-like depositions on
which various epithelial cells
membrane rest & are cell associated

collagen reticular
fibers and fibers and Blood
bone ground plasma
mineral substance
Loose
Bone tissue connective Blood
tissue
 Composition of Extracellular Matrix (ECM)

Molecules found in ECM

Fibrous Proteins Proteoglycans
▪ Collagen ▪ Hyaluronic acid
▪ Elastin ▪ Heparan sulphate
▪ Fibronectin ▪ Chondroitin sulphate
▪ Laminin ▪ Keratan sulphate
o Found in varying amounts in
o Glycosaminoglycans attached to
different tissues
extracellular matrix proteins →
o Produced by ‘fibroblasts’ and
released as ‘precursor’ Proteoglycans
molecules o Have net negative charge → attracts
o Incorporation into different sodium and water molecules & keeps
tissues is guided by fibroblasts matrix and resident cells hydrated
based on the functional needs o Helps to trap and store growth factors
 Structure of Extracellular Matrix (ECM)

Microfilament
Phospholipid
Bilayer

Fibronectin Integrin

Collagen Proteoglycan

Elastin

➢ The extracellular matrix is made up of proteoglycans, water, minerals,

and fibrous proteins
➢ Their composition, architecture and bioactivity greatly vary from tissue
to tissue in relation to the specific role the ECM is required to assume
 Production of components of Extracellular Matrix (ECM)

components of the (fiber-making cells) are charged

extracellular matrix with this responsibility
are produced and Chondrocytes → cartilaginous
organized by the cells matrix & Osteoblasts → bone
that live within it formation
• Components of the ECM are produced intracellularly by resident
cells and secreted into the matrix via exocytosis
• Once secreted, they then aggregate with the existing matrix
Many cell types contribute
to the development of
various types of
extracellular matrix found in
plethora of tissue types
 Proteoglycan component of Extracellular Matrix

➢ STRUCTURE OF PROTEOGLYCANS
 Proteoglycans usually consist of a core protein covalently
linked to a glycosaminoglycan (GAG)
 Glycosaminoglycan typically consists of a long
polysaccharide chain with a repeating disaccharide motif
 Proteoglycan monomers typically are bound non-covalently
to a hyaluronic acid molecule in association with linker proteins
in a “bottle brush” arrangement
Repeating disaccharide is linked to a serine residue on the
protein through a galactose-galactose-xylose-serine
sequence by glycosidic linkage
Proteoglycans role in Extracellular Matrix

Polyanionic - negative
Structural charge comes from the
Lubricant role
components presence of carboxyl
and/or sulfate groups

Hydration - bind
large amounts of Cell/Cell signaling Cell/Cell adhesion
water
 Characteristics of Proteoglycans in Extracellular Matrix
Name of Characteristics Occurrence / Importance
Glycosaminoglycan
Heparan Sulphate 2 or 3 HS chains are In this form HS binds to a variety of protein
(HS) → Linear attached in close ligands and regulates a wide variety of
polysaccharide proximity to cell biological activities→ developmental
occurring in surface or ECM processes, angiogenesis, blood
proteoglycan proteins coagulation, and tumour metastasis

Chondroitin Contribute to the Cartilage, tendons, ligaments, and walls of

Sulphate (CS) tensile strength the aorta
 Characteristics of Proteoglycans in Extracellular Matrix
Name of Characteristics Occurrence / Importance
Glycosaminoglycan
Keratan Sulphate Variable sulfate Cornea, cartilage, bones, and the horns
(KS) content and do not of animals
contain uronic acid
Hyaluronic acid In extracellular space, Load-bearing joints
(HA) → non- it confers upon tissues Interstitial gel
proteoglycan the ability to resist Inner surface of cell membrane
polysaccharide compression by Acts as an environmental cue that
providing a regulates cell behavior during
counteracting turgor embryonic development, healing
(swelling) force by processes, inflammation, and tumor
absorbing significant development
amounts of water
 Protein component of Extracellular Matrix (ECM)

Collagen
Most abundant protein in ECM
Structure – triple helix
Long & slender molecule

Divided into 5 families according to the

19 varieties have been identified types of structures they form
 Collagen of Extracellular Matrix

Collagen Distribution
Type I All regions of the body
Type II Cartilage and vitreous humor
Type III Skin, lung and vascular tissues
Type IV Basement membranes
➢ Composition: about 1000 amino acids
➢ Every third amino acid is ‘Glycine’ (33%) Composition of
➢ ( – X – Y – Gly - )n Collagen
➢ Y = Proline or Hydroxyproline
➢ Other amino acids present – Lysine, Hydroxylysine, Arginine & Alanine
 Collagen of Extracellular Matrix

➢ Characteristics of Collagen
 Diameter: 2 - 10 micrometer
 Run randomly in various directions
 In many parts, collagen fibers lie parallel to each other forming
bundles of various sizes
 Flexible but inelastic (non-extensible)
 Pink colour with H & E stain

Disorders such as Ehlers Danlos Syndrome, Marfan’s syndrome,

Menkes disease, scurvy, osteogenesis imperfecta, and
epidermolysis bullosa are linked with genetic defects in collagen-
encoding genes
Synthesis of Collagen
Fibroblasts

Vitamin C

ECM → cleaved
by specific
peptidases to
form
tropocollagen

Procollagen
Mature collagen
fibrils →
aggregates
 Elastin of Extracellular Matrix (ECM)

❑ Diameter 2 - 10 micrometer

❑ Branch & rejoin to form loose network

❑ Highly elastic → can stretch one and half time their original
length

❑ Distribution: Found in lungs, skin, large arteries, ligamenta

flava (connecting laminae of successive vertebrae)
 Elastin of Extracellular Matrix (ECM)

❑ Composition: Glycine (1/3rd), Proline,

Hydroxyproline and Alanine

❑ Major cross-linking – ‘Desmosine’,

formed from 4 lysine residues

❑ Function: Provides elasticity and

extensibility to the tissues
Disorders such as Cutis laxa, Copper deficiency,
Pseudoxanthoma Elasticum and Williams syndrome are
associated with deficient or absent elastin fibers in the ECM
 Fibronectin & Laminin of Extracellular Matrix (ECM)

Fibronectin Laminin
• connect cells with collagen fibers in • found in the basal
the ECM laminae
• bind collagen and cell-surface • form networks of web-like
integrins structures that resist
• facilitate cell movement → allows tensile forces in the basal
their movement through ECM – lamina
important in wound healing and • assist in cell adhesion
tissue repair

❖ Cell linkage molecules

Functions of Extracellular Matrix (ECM)

Forming an essential support structure for cells

Controlling communication between cells

Segregating tissues

Regulating cell processes such as growth, migration

and differentiation
 Changes in the ECM in Healing after Injury
First response to injury or vascular damage
Monocytic infiltration to the damaged ECM Formation of fibrin clot

Differentiation into macrophages

Secretion of growth factors, cytokines Favor angiogenesis, fibroblast
and Matrix metalloprotease (MMPs) migration, and proliferation

Fibroblasts lay down ECM proteins

Trans-differentiation of fibroblasts to Deposition of ECM and synthesis of
other types of cells (myofibroblasts)… collagen bundles

The remodeled ECM will promote migration of cells to the wound site →
initiates the healing process
Changes in the ECM in during Aging

• Junction proteins  with age → gaps

Stiffening of ECM
occur at junction between cells

Matrix metalloproteinase (MMP)

• Thinning of basement
– mediated degradation is
membrane
enhanced

Fibroblasts becomes senescent

•  Mitochondridial ROS
→ Express more cytokines,
MMPs and plasminogen → chronic
activator inhibitor (PAI) inflammation state
Changes in the ECM in during Aging

➢ The net effect is the destruction of the integrity of the

elastin network and basement membrane

➢ Inappropriate collagen cross-linking induced by

the ROS, and enhanced glycation results in the
stiffening of tissues

➢ Aged tissue is less elastic, rigid, and mechanically

weaker
 Abnormalities in ECM

Osteogenesis Imperfecta
➢ Inheritance: dominant trait
➢ Cause: mutation which results in the replacement of a single glycine
residue by cysteine in type I collagen
➢ Result: disrupts the triple helix near the carboxy terminus, hence the
polypeptide becomes excessively glycosylated and hydroxylated
➢ Outcome: brittle bones leading to multiple fractures and skeletal
deformities
Abnormalities in ECM
Ehlers–Danlos Syndrome
➢ The condition results from defective type III collagen
formation due to defective lysyl oxidase or lysyl
hydroxylase
➢ It is characterized by weakening of collagen, loose skin,
hypermobile, and lax joints
 Abnormalities in ECM
Marfan Syndrome
➢ Inheritance: autosomal dominant
➢ Characteristics: Arachnodactyly (long digits), ectopia lentis
(dislocation of lens), hyperextension of joints, and aortic
aneurysm
➢ Defect: in the gene, coding for a connective tissue protein,
fibrillin-1
➢ Implication: It is a component of microfibrils, which
normally gives the substratum for deposition of elastin →
fibrillin and elastin are deposited at lower concentrations
Abnormalities in ECM
Menkes Disease
Deficiency of copper results in defective function of lysyl
oxidase, and reduced cross-linking of collagen results

Deficiency of Ascorbic Acid

It is characterized by the defective hydroxylation of collagen.
The collagen formed is weak, leading to fragility of blood
vessels, poor wound healing, etc
 Abnormalities in ECM

Pseudoxanthoma Elasticum
It is an inherited defect in the formation of elastin.
Clinical manifestations are similar to Ehlers–Danlos syndrome

Copper Deficiency
Copper deficiency blocks the formation of aldehydes, which
are essential for cross-linking.
Some lysine residues are oxidized by copper containing lysyl
oxidase