Tissues 3- Extracellular matrix biology 1

Question 1

What is the extracellular matrix

Answer 1

A complex network of proteins and carbohydrates filling spaces between cells- deposited by cells, that becomes immobilised and fills the space between cells.
It comprises both fibrillar and non-fibrillar components

Question 2

What are the functions of the extracellular matrix

Answer 2

Provides physical support
Determines the mechanical and physicochemcial properties of the tissue
Influences the growth, adhesion and differentiation status of the cells and tissues with which it interacts
Essential for development, tissue function and organogenesis.
Connective tissues are rich in ECM.

Question 3

What is the basal lamina

Answer 3

A special type of ECM

Question 4

What type of cells are embedded in the ECM

Answer 4

Macrophages and fibroplasts

Question 5

Describe the components of connective tissues

Answer 5

All connective tissues contain a distinct spectrum of collagens, multi-adhesive glycoproteins and proteoglycans (extracellular matrix) together with a cellular component
Matrix components interact with specific cell surface receptors

Question 6

Describe the types of collagen found in the ECM of connective tissues

Answer 6

Type I, II, III (fibrillar)
Type IV (basement membrane)

Question 7

Describe the types of multi-adhesive glycoproteins in the ECM of connective tissues

Answer 7

Fibronectin, Fibrinogen

Laminins (basement membrane)

Question 8

Describe the types of proteoglycans found in the ECM of connective tissue

Answer 8

Proteoglycans
Aggrecan, Versican, Decorin
Perlecan (basement membrane

Question 9

Describe some of the human disorders caused by ECM abnormalities due to gene mutations affecting matrix proteins

Answer 9

Gene mutations affecting matrix proteins
e.g. osteogenesis imperfecta - Type I collagen
Marfan’s syndrome - Fibrillin 1
Alport’s syndrome - Type IV collagen (5)
Epidermolysis Bullosa - Laminin 5 (in all 3 chains)
Congenital Muscular Dystrophy- Laminin 2 (2 chain

Question 10

Describe some of the human disorders caused by ECM abnormalities due to gene mutations affecting ECM metabolism

Answer 10

e.g. Hurler’s syndrome - L--iduronidase

other “mucopolysaccharidoses” (inability to degrade GAGs)

Question 11

Describe fibrotic disorders due to excessive ECM deposition

Answer 11

e.g. Liver fibrosis - cirrhosis
Kidney fibrosis - diabetic nephropathy
Lung fibrosis - silicosis
However, fibrosis can affect any organ.

Question 12

Describe disorders due to the excessive loss of ECM

Answer 12

. Disorders due to excessive loss of ECM

e.g. osteoarthritis

Question 13

Describe the varied properties of connective tissues

Answer 13

Tendon and skin: tough and flexible
Bone: hard and dense
Cartilage: resilient and shock-absorbing
Vitreous humour (jelly that fills interior of the eye): soft and transparent
Different types of collagen and arrangements of oriented collagen, as well as which other ECM components are present- different quantities of collagen too.

Question 14

What are collagens

Answer 14

Family of fibrous proteins found in all multicellular organisms
Major proteins in bone, tendon and skin
Are the most abundant proteins in mammals, constituting 25% of total protein mass

Question 15

How many different types of collagen are there

Answer 15

28 collagen types exist in humans, designated by roman numerals
There are 42 genes encoding collagens in humans
More genes- due to different alpha chains which make up collagen

Question 16

Describe the molecular composition of collagen

Answer 16

Each collagen molecule comprises three  chains, forming a triple helix.
Can be composed of one or more different  chains
Type I collagen has chains from two different genes - its composition is [1(I)]2 [2(I)]
Types II and III collagen have only one chain type – their compositions are, therefore, [1(II)]3 and [1(III)]3

Question 17

Describe the collagen triple helix

Answer 17

Characteristic gly-x-y repeat: x is often proline, y is often hydroxyproline
In fibrillar collagens, each  chain is approximately 1000 amino acids, forming a left-handed helix

Question 18

Why does the 3rd amino acid have to be glycine.

Answer 18

Three  chains form a stiff triple helical structure – every third position must be occupied by glycine, as this is the only amino acid small enough to occupy the interior.

Question 19

Describe the assembly of collagen into fibres

Answer 19

one  chain
three  chains
collagen fibril
collagen fiber

Question 20

Describe collagen biosynthesis

Answer 20

Alpha chains are synthesised as longer precursors, pro-alpha chains, by ribosomes on the RER.
Inside the ER/Golgi Body- pro-alpha chains undergo a series of covalent modifications ( hydroxylation of selected prolines and lysines, glycolysations of selected hydroxylysines) to form triple-helical procollagen (N and C terminal polypeptides).
Secretion
Extracellular peptidases remove propeptides from procollagen- allowing collagen to associate laterally to form fibrils.
Cross-links to form fibres.

Question 21

Describe lysine and proline hydroxylation

Answer 21

Prolyl and lysyl hydroxylases require Fe2+ and vitamin C
Contributes to interchain hydrogen bond formation.
Lysine and hydroxylysine are also modified in the formation of covalent crosslinkages. This takes place only after the collagen has been secreted.
Vitamin C-deficiency results in underhydroxylated collagens, with dramatic consequences for tissue stability (scurvy).

Question 22

Describe the importance of the intermolecular covalent links

Answer 22

Provides tensile strength and stability. Both lysine and hydroxy-lysine residues are involved. The type and extent of cross-links is tissue specific and changes with age.
Gap regions- point of weakness- reduce length of these.

Question 23

In how many directions do parallel bundles resist tensile forces

Answer 23

1- in tendons- collagen forms fibrils along the major axis of tension

Question 24

Describe how collagen is arranged in the skin

Answer 24

The collagen fibres are arranged perpendicularly in one direction- to resist tensile stress in multiple directions. Fibroblasts work on the collagen they secrete, rearranging it into different arrangements, crawling over it and pulling on it to arrange it into different sheets.

Question 25

What are the non-fibrillar collagens

Answer 25

Fibril-associated collagens (e.g types IX and XII) associate with fibrillar collagens and regulate the organisation of collagen fibrils- link fibrils to one another and to other components of the ECM
Type IV collagen is a network-forming collagen and is present in all basement membranes, though its molecular constitution varies from tissue to tissue.

Question 26

Describe collagen IV assembly

Answer 26

Type IV collagen molecules assemble into a sheet-like network – an essential component of basement membranes.
Monomer- dimer-tetramer- supramolecular molecule.

Question 27

Describe the role of elastic fibres

Answer 27

Whereas collagens are important for the tensile strength of tissues, elastic fibres are important for the elasticity of tissues, such as skin, blood vessels and lungs. Often, collagen and elastic fibres are interwoven to limit the extent of stretching.

Question 28

What are elastic fibres made up of

Answer 28

Elastic fibres consist of a core made up of the protein elastin, and microfibrils, which are rich in the protein fibrillin.
Elastin is an unusual protein consisting of two types of segments that alternate along the polypeptide chain: hydrophobic regions, and -helical regions rich in alanine and lysine. Many lysine side chains are covalently cross-linked.

Question 29

Describe Marfan’s syndrome and fibrillin-1

Answer 29

Elastic fibers: integrity depends on microfibrils, containing the protein fibrillin
Marfan’s syndrome: mutation in fibrillin-1. Many different mutations

Diverse manifestations, involving primarily the skeletal, ocular, and cardiovascular systems. Predisposed to aortic ruptures.

Question 30

What are basement membranes

Answer 30

Basement membranes (BMs; also called basal laminae) are flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes

Question 31

Describe the regulation of tissue function by BMs

Answer 31

BMs surround muscle, peripheral nerve and fat cells and underlie most epithelia.
BMs are highly specialized extracellular matrices containing distinct spectra of collagens, glycoproteins and proteoglycans.
Separation of cells from underlying connective tissue

Question 32

Describe the role of the BM in the kidney glomerulus

Answer 32

Highly selective filter

Question 33

What is diabetic nephropathy

Answer 33

ECM accumulation
Impinges on capillaries, restricting renal filtration
Renal failure
Thickened BM

Question 34

What is Alport syndrome

Answer 34

Due to mutations in collagen IV
Progressive loss of kidney function and hearing loss
Due to abnormally split and laminated BM

Question 35

What do basement membranes consist of

Answer 35

Type IV collagen and laminins

Question 36

Why is it important that collagen is not assembled in the cell

Answer 36

The cell would become choked with collagen

Question 37

Which two types of cell synthesise collagen

Answer 37

Fibroblasts- skins, tendons and other connective tissues

Osteoblasts- bone