OMG Lecture 40: The extracellular matrix Flashcards

Tuesday 21st January 2025

1
Q

Is it true that eukaryotic cells exist in a physical environment?

A

Yes. (Cell-cell junctions + Extracellular Matrix)

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2
Q

Is it true that that the extracellular matrix is a major product of the secretory pathway?

A

Yes

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3
Q

Why is the extracellular matrix important?

A
  • Holds the cells together and anchors their cytoskeleton
  • Provides the environment where cells interact or move
  • The matrix composition is different in different tissues
  • In animals, it’s made of proteins and polysaccharides
  • Present in dense connective tissues (bone/teeth, tendons, exoskeleton of arthropods, shells of molluscs)

(The matrix is thick and has a primary mechanical role
)

  • And in lose connective tissues (over epithelium, gut, skin, eyes - cornea)

(The matrix is thin, cells are connected by cell-cell junctions ; Links cytoskeleton to extracellular structures
)

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4
Q

What does the extracellular matrix do?

A
  • Scaffolding role supporting cells, as provides strength, elasticity, turgor).
  • Influences cell behaviour, e.g. survival, development, migration, shape, proliferation, and function.
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5
Q

What is turgor?

A

The internal ‘tension’ in a tissue

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6
Q

In isotonic conditions…

A

flaccid

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7
Q

In hypotonic conditions…

A

Turgid

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8
Q

In the ECM, what does the turgor help to do?

A

In the ECM, it helps absorb impact and provides scaffolding for the cells in tissues

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9
Q

Where are ECM molecules produced?

A

Locally

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10
Q

ECM molecules are secreted by fibroblasts in…

A

Secreted by fibroblasts in loose CT

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11
Q

ECM molecules are secreted by osteoblasts in…

A

Secreted by osteoblasts in bone

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12
Q

ECM molecules are secreted by chondrocytes in…

A

Secreted by chondrocytes in cartilage

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13
Q

Spaces around cells are filled with secreted molecules that form a gel…

A

POLYSACCHARIDES
Glycosaminoglycans (GAG)/proteoglycans (e.g. hyaluronan TURGOR, dermatan sulfate TISSUE DEVELOPMENT)
PROTEINS
Fibrous proteins (e.g. collagen STRENGTH, elastin ELASTICITY)
Glycoproteins (fibronectin REGENERATION)

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14
Q

Does turgor help plant cells to absorb impact?

A

Yes

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15
Q

What are Glycosaminoglycan (GAG) chains?

A
  • Glycosaminoglycan (GAG) chains are repeated units of negatively charged (-) disaccharides that form very long linear chains.

-They attract cations (Na+) causing large amounts of water to be sucked into the matrix - hydration. This creates turgor

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16
Q

Hyaluronan (hyaluronic acid)…

A

Resists compressive forces in tissues and joints

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17
Q

Dermatan sulfate…

A
  • Assembly of collagen
  • Essential for tissue development
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18
Q

What are the other main types of polysaccharides/ Glycosaminoglycans (GAGs) in the ECM?

A
  • Heparan sulfate
  • Keratan sulfate
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19
Q

Is it true that all Glucosaminoglycans and proteoglycans are synthesised in and secreted by cells that are within the ECM?

A

Yes

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20
Q

Proteoglycans…

A
  • PROTEIN TRANSLOCATION in the ER
  • Addition of the precursor oligosaccharide in the ER
  • SECRETORY PATHWAY
  • Modification of the oligosaccharide chain in the Golgi
  • Exocytosis or anchoring in plasma membrane (syndecans)
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21
Q

Proteoglycans are translocated into the ER and checked for correct folding, before entering the secretory pathway.

A

Proteoglycans are translocated into the ER and checked for correct folding, before entering the secretory pathway.

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22
Q

Give an example of proteoglycans

A

Syndecans

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23
Q

What does syndecan do?

A

Regulates cell-matrix adhesions and influences cell behaviour

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24
Q

What are syndecans?

A

Syndecans are transmembrane proteoglycans, meaning they span the cell membrane and help connect the cell to its environment.

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25
Q

What are the 3 main domains that syndecans consist of?

A
  • C-terminal cytoplasmic domain (CD) – Inside the cell, helps with signaling.
  • Transmembrane domain (TM) – Anchors the syndecan in the cell membrane.
  • Extracellular domain (ED) – Extends outside the cell and interacts with molecules in the ECM.
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26
Q

What chains do syndecans have attached to them?

A

Syndecans have heparan sulfate (HS) chains attached to them.

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27
Q

What are heparan sulfate (HS) chains?

A

HS chains are a type of glycosaminoglycan (GAG) that interacts with various molecules in the ECM.

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28
Q

What’s the function of syndecans?

A
  • Act as co-receptors or activators
  • The HS chains can bind to:
  • Growth factors (e.g., FGF – Fibroblast Growth Factor), enhancing their signaling.
  • ECM components (e.g., fibronectin, collagen) to help cell adhesion and communication.
  • Also, signal transduction
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29
Q

How can syndecans carry out signal transduction?

A
  • The TM (transmembrane) and ED (extracellular) domains help transmit signals from the ECM to the cell.
  • This influences cell behavior, differentiation, and response to the environment.
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30
Q

Summary of syndecans

A

Syndecans are transmembrane proteoglycans that link cells to the ECM.

They have heparan sulfate (HS) chains, which help in binding growth factors and ECM molecules.

They function as co-receptors and are involved in cell signaling.

The extracellular matrix is dynamic, influencing cell behavior and communication.

31
Q

The extracellular matrix (ECM) is not just a structural material but plays an active role in cell communication and regulation!

A

The extracellular matrix (ECM) is not just a structural material but plays an active role in cell communication and regulation!

32
Q

Describe the ECM composition

A
  • Diverse components, different pore sizes, and molecule charges
  • Different hydration levels, different cell turgor and ECM transport
33
Q

Are the ECM components very big?

34
Q

Components of the ECM are polysaccharides AND proteins

A

Components of the ECM are polysaccharides AND proteins

35
Q

What is an example of a fibrous ECM protein?

36
Q

What pervcentage of the protein in the body is collagen

37
Q

How many known types of collagen are there?

A

More than 20

38
Q

How many amino acids long is collagen?

A

300aa long

39
Q

Is it true that in the ER, there are multiple modifications as the molecule is being translated?

40
Q

In the ER, what modifications are made to collagen as collagen is being translated?

A
  • Modifications improve the solubility of the pro-collagen
  • About 50% of the proline residues are hydroxylated (-OH) by collagen prolyl-hydroxylases - this requires vitamin C
  • Specific lysine residues are hydroxylated ( ) – this also requires vitamin C
  • The C-terminal domains are N-glycosylated ( )
  • And, mostly in the Golgi, some of the hydroxylysyls are O - glycosylated by addition of galactose ( ) or a glucose-galactose disaccharide ( )
41
Q

In the ER, how do the C terminal domains of monomers trimerise ?

A

Via disulfide bonds

42
Q

IS it true that winding produces a stiff triple stranded helical structure with highly soluble N and C termini/

43
Q

What is Hsp47?

A

a collagen-specific chaperone that aids the winding

44
Q

What are the functions of the N and C terminal propeptides?

A
  • One other function of the N and C propeptides is to keep the trimers apart: this stops them forming fibrils …
    … until late in the secretory pathway, when the propeptides are removed, forming tropocollagen
45
Q

How do fibrils form prior to secretion?

A
  • Individual tropocollagens are crosslinked (covalent intra- and inter-molecular covalent cross-linking between hydroxylysyls) to form fibrils.
  • Individual tropocollagens are crosslinked (covalent intra- and inter-molecular covalent cross-linking between hydroxylysyls) to form fibrils.
46
Q

Describe fibripositors…

A
  • Fibripositors are tubular extensions at the plasma membrane that accept GPCs (Golgi to PM carriers) containing collagen
  • A closed fibripositor opens by fusing with the PM, and the collagen fibril is extruded out of the cell
  • The fibrils line up in the ECM, in register
47
Q

How is collagen arranged in the skin?

A
  • Collagen fibrils in skin are arranged like wickerwork:
  • This is (partly) why (young) skin springs back into shape … but with age … (oh, dear)
48
Q

How is collagen arranged in the bone?

A
  • Collagen fibrils in bone have a “plywood” arrangement that does not allow stretching
  • This is (partly) why bone is stiff, strong, tough and lightweight (it is also helped by mineralisation)
49
Q

How is collagen arranged in tendons?

A
  • And in tendons, collagen fibrils aggregate to form a fibre (a supercable!) …
  • This is why tendons can be stretched without breaking
50
Q

What is a tendon?

A

a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone.

51
Q

Why is collagen highly processed in the ER and the golgi?

A

To make the collagen more soluble and to prevent the aggregation of monomers.

52
Q

Where do PM carriers take collagen>

A

from the golgi to the EM

53
Q

How can collgane form so many differnt arrangemets?

A

Because the fibrils are easily arranegd

54
Q

What makes up the basement lamellae?

A
  • Type IV collagen forms X-shaped complexes that combine to form a network
  • Laminin: cross shaped
  • Perlecan: long, snaky proteoglycans
  • Plus smaller Proteoglycans that fill in the spaces
55
Q

What are basement lamellae?

A

Basement lamellae are dense sheets of interacting proteins.

56
Q

What does the hydroxylation of collagen require?

57
Q

What happens with reduced collagen hydroxylation?

A

With reduced hydroxylation, collagen is mis-formed: connective tissue problems arise, such as scurvy

58
Q

What deficiency causes scurvy?

59
Q

Name some collagen disorders

A
  • Osteogenesis imperfecta/brittle bone disease
  • Type I collagen alteration
  • Schmidt-type chondrodysplasias
  • Type X collagen alteration
  • Ehlers-Danlos syndromes

-

60
Q

Describe elastin

A

A hydrophobic elastic protein, with extensive crosslinks, highly prevalent in the ECM of arteries (50% dry weight of the aorta). Gives tissues their elasticity.

61
Q

Is elastin a fibrous protein?

62
Q

Can fibronectin be described as ‘sticky’?

64
Q

Fibronectin has multiple domains for binding to….

A
  • to itself
  • to other ECM molecules
  • and also to integrins/cell receptors
65
Q

How does the cytoskeleton interact with fibronectin to produce tension?

A

Since the cytoskeleton is (indirectly) connected to ECM molecules, the cell can contract and pull on the fibronectin in the matrix to create tension

66
Q

Is the basal lamina a very important extracellular matrix?

67
Q

Describe the basal lamina

A
  • Basal lamina is a specialized type of ECM also known as basement membrane
  • 40-120nm thick and lies beneath epithelial cells
  • Allows mechanical connection
  • Is synthesized by cells around it
  • Contains glycoproteins laminin, type IV collagen and nidogen
68
Q

Is it true that the basal lamina allows mechanical connection of cells in the connective tissue?

69
Q

Is it true that cells degrade the ECM matrix as well as making it?

70
Q

Describe how cells degrade the ECm

A
  • When cells divide they need to stretch out (which requires them to cut into the ECM)
  • When cells migrate through connective tissue localised degradation of ECM is required e.g. white blood cells moving through the basal lamina of a blood vessel to get to tissues in response to infection
  • Matrix degradation is also needed in tissue repair and tissue remodelling
  • The proteases responsible (matrix metalloproteases and serine proteases) must be tightly controlled if the body isn’t to collapse!!
  • This is achieved by local activation, confining these enzymes to cell surfaces, and by secreting potent inhibitors
71
Q

The ECM and cancer

A
  • The tight binding of the cytoskeleton to the ECM means that cells can control the shape (and content) of the ECM: however, that tight binding implies that for cell movement and division, cells must let go of and degrade the ECM
  • Cancer cells often down-regulate fibronectin, so they have weak contacts with the ECM: this makes it easier to divide in an uncontrolled manner, and allows cancerous cells to migrate more easily: it permits metastasis
  • The matrix metalloproteinases are also required for tumour invasion and neoangiogenesis as well as metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy
72
Q

SUMMARY

A
  • Cells in connective tissues are embedded in an ECM. ECM molecules may influence these cells (e.g. activating signalling pathways)
  • Glycosaminoglycans and proteoglycans form hydrated gels and provide turgor, support and a medium for cell migration
  • Fibres strengthen and shape the matrix and provide surfaces for cells to stick to (next lecture)
  • Fibres are composed of rope-like (or mesh-like) collagens and stretchy elastins
  • Sticky fibronectins help organise the matrix molecules and help bind cells
  • The cytoskeleton (next lecture) indirectly connects with ECM molecules and influences the way these are organised
  • Local cells can also degrade ECM components in a regulated manner