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POM (Principles of Medicine) > Extracellular matrix > Flashcards

Extracellular matrix Flashcards

1
Q

What is an extracellular matrix?

A

A complex network of proteins and carbohydrates filling spaces between cells

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2
Q

What is the extracellular matrix made up of?

A

both fibrillar and non-fibrillar components

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3
Q

What are the 4 key functions of the extracellular matrix?

A
  • Provides physical support
  • Determines the mechanical and physicochemical 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
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4
Q

What is connective tissue made up of?

A

Extracellular matrix and component materials

components: versican and laminin

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5
Q

What are connective tissues made up of?

A

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

Multi-adhesive glycoproteins
Fibronectin, Fibrinogen
Laminins (basement membrane)

Proteoglycans
Aggrecan, Versican, Decorin
Perlecan (basement membrane)

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6
Q

What are the human disorders resulting from ECM abnormalities?

A
  1. Gene mutations affecting matrix proteins
  2. . Gene mutations affecting ECM catabolism
  3. . Fibrotic disorders due to excessive ECM deposition
  4. Disorders due to excessive loss of ECM
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7
Q

What are collagens?

A
  • Family of fibrous proteins
  • Major proteins in bone, tendon and skin
    ( most abundant proteins)
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8
Q

How are collagen fibrils aligned in the skin as well as mature bone and cornea?

A

successive layers nearly at right angles to each other

These tissues resist tensile force in all directions

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9
Q

molecular arrangements of collagen fibres?

A

Each collagen molecule comprises three α chains, forming a triple helix.

Can be composed of one or more different α chains

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10
Q

What is the composition of collagen I ?

A

has chains from two different genes - its composition is [α1(I)]2 [α2(I)]

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11
Q

What is the composition of collagen II and III ?

A

have only one chain type – their compositions are, therefore, [α1(II)]3 and [α1(III)]3

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12
Q

What is the arrangement of an α chain?

A

characteristic gly-x-y repeat

x- often proline) (y- often hydroxyproline

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13
Q

How are collagen fibres assembled?

A

one α chain –>
3 α chains –>
collagen fibril –>
collagen fibre

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14
Q

What do all newly synthesised collagen chains have?

A

non-collagenous domains at N- and C-termini.

but after secretion they are usually removed

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15
Q

Collagen biosynthesis pathway?

A

Procollagen –>
Collagen –>
Fibril formation –>
Cross-linking

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16
Q

Fibrillar collagen biosynthesis

A

synthesis of pro-a chain –>
hydroxylation of selected prolines and lysines –>
glycosylation of selected hydroxylysines –>
self-assembly of the pro-a chains –>
procollagen triple-helix formation –>
secretion (through secretory vesicles or into the ER/ Golgi compartment) –> (procollagen molecule)
cleavage of propeptides –>
(collagen molecule) self-assembly into fibril –>
(collagen fibril) aggregation of collagen fibrils to form a collagen fibre

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17
Q

What does crosslinking provide?

A

tensile strength and stability

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18
Q

What is involved in cross-linking?

A

Both lysine and hydroxy-lysine residues are involved

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19
Q

What is the extent of cross-links?

A

the type and extent is tissue specific and changes with age

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20
Q

What do prolyl and lysyl hydroxylases require?

A

Fe2+
vitamin C

contribute to interchain hydrogen bond formation

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21
Q

What does Vitamin C deficiency result in?

A

underhydroxylated collagens, with dramatic consequences for tissue stability (scurvy)

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22
Q

What is ehlers-danlos syndromes (EDS)?

A

a group of inherited connective tissue disorders whose symptoms include stretchy skin and loose joints

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23
Q

What do mutations in collagen affect?

A
  • collagen production
  • collagen structure
  • collagen processing
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24
Q

Not all collagen form fibrils

A

Fibril-associated collagens associate with fibrillar collagens and regulate the organisation of collagen fibrils

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25
Q

What is the basement membrane formed from?

A

flexible-sheet like multilayered network

type IV collagen

26
Q

What is the role of basement membranes?

A

regulators of tissue function

27
Q

What are basement membranes?

A

are flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes
- contain a distinct repertoire of collagens, glycoproteins and proteoglycans

28
Q

What do basement membranes surround?

A

muscle, peripheral nerve and fat cells and underlie most epithelia

29
Q

What do they form an important part of in the kidney?

A

filtration unit as the Glomerular basement membrane (GBM)

30
Q

What is the disorder diabetic nephropathy?

A

there is an accumulation of extracellular matrix leading to a highly thickened basement membrane. This restricts renal filtration and can lead to renal failure

31
Q

What is Alport syndrome?

A

mutations in collagen IV result in an abnormally split and laminated GBM which is associated with a progressive loss of kidney function and also hearing loss

32
Q

Are elastic fibres usually found by themselves?

A

no, collagen and elastic fibres are interwoven to limit the extent of stretching

33
Q

What do elastic fibres consist of?

A

a core made up of the protein elastin, and microfibrils, which are rich in the protein fibrillin

34
Q

What is Marfan’s syndrome?

A

Mutations in the protein fibrillin-1

skeletal, ocular, and cardiovascular systems are affected

35
Q

What is elastin?

A

unusual protein consisting of two types of segments that alternate along the polypeptide chain: hydrophobic regions, and α-helical regions rich in alanine and lysine
-Many lysine side chains are covalently cross-linked

36
Q

What are some examples of multi-adhesive glycoproteins?

A

Laminins (associated with basement membranes)

fibronectin

37
Q

How are extracellular matrix proteins organised?

A
  • Most ECM proteins are very large
  • composed of characteristic protein domains of 50-200 amino acids
  • multifunctional: modular structure
    • multi-adhesive, binding various matrix components and cell-surface receptors
38
Q

What are lamins?

A

heterortrimeric proteins made up of an α chain, a β chain and a γ chain, which form a cross shaped molecules
- very large proteins

39
Q

What is the role of lamilins?

A
  • multi-adhesive proteins which can interact with a variety of cell surface receptors including integrins and dystroglycan
  • self-associate as part of the basement membrane matrix
  • interact with other matrix components
40
Q

What are the diseases from typical mutations in lamilin?

A

muscular dystrophy and epidermolysis bullosa

41
Q

What are fibronectins?

A

a family of closely related glycoproteins of the extracellular matrix which are also found in body fluids
- multi-adhesive proteins

42
Q

How can fibronectins exist?

A

insoluble fibrillar matrix or as a soluble plasma protein

43
Q

From how many genes are fibronectins derived?

A

from a single gene, with alternate splicing of mRNAs giving rise to the different types

44
Q

What are the bonds in laminin?

A

large multidomain molecule linked together by disulphide bonds

45
Q

What are the roles of laminins?

A

regulating cell adhesion and migration in a variety of processes, notably embryogenesis and tissue repair
- promote blood clotting

46
Q

What does laminin link to?

A

between the matrix and cytoskeleton

47
Q

What are proteoglycans?

A

core proteins to which are covalently attached one or more glycosaminoglycan (GAG) chains

48
Q

What are GAG chains made up of?

A

repeating disaccharide units with one of the two sugars being an amino sugar
- many are sulfated or carboxylated, and as a result carry a high negative charge

49
Q

What does the negative charge on GAG chains attract?

A

a cloud of cations including Na+, resulting in large amounts of water being sucked into the extracellular matrix

50
Q

What are the different proteoglycan families? (4)

A
  1. Basement membrane proteoglycans
  2. Aggregating proteoglycans
  3. Small leucine-rich proteoglycans
  4. Cell surface proteoglycans
51
Q

What is cartilage made up of?

A

matrix rich in collagen with large quantities of GAGs trapped within the meshwork

52
Q

What are the 4 groups of GAG chains?

A
  1. Hyaluronan
  2. Chondroitin sulfate and dermatan sulfate
  3. Heparan sulfate
  4. Keratan sulfate
53
Q

What is hyaluronan? (hyaluronic acid)

A

a carbohydrate chain without a core protein
(is distinct form the other GAGs)
It is unsulfated and made up of repeating disaccharides which can number up to 25,000 sugars

54
Q

Where is hyaluronan found?

A

in the extracellular matrix of soft connective tissues

– vitreous humour of the eye and in synovial fluid of joints

55
Q

What is aggrecan?

A

major constituent of the cartilage extracellular matrix

56
Q

What is the structure of aggrecan?

A

the GAGs are highly sulfated, increasing their negative charge
- also contain large numbers of negatively carboxyl groups

57
Q

What do the multiple negative charges on aggrecan attract?

A

cations such as Na+ that are osmotically active –>large quantities of water retained by the highly negatively charged environment

58
Q

Why is aggrecan perfectly suited to resist compressive forces?

A

Under compressive load, water is given up, but regained once the load is reduced

59
Q

What are the disorders resulting from ECM abnormalities?

A

osteoarthritis

fibrotic disease

60
Q

What is osteoarthritis?

A

an erosive disease resulting in excessive extracellular matrix degradation
(loss of cartilage)

61
Q

What happens with aggrecan with age?

A

it is cleaved by aggrecanases and metalloproteinases

–> loss of aggrecan fragments to the synovial fluid

62
Q

What is fibrotic disease?

A

a result of an excessive production of fibrous connective tissue

POM (Principles of Medicine) (17 decks)

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