L10: ECM Homeostasis

Question 1

How is a healthy ECM is maintained?

Answer 1

• by cells within ECM that secrete components of the ECM
• the same cells also secrete metalloproteinases which digest/ breakdown these components to remove damaged matrix
• ECM components feedbacking via receptors (integrins/ PRR) to effect synthesis and control MPs

Question 2

Why is ECM component breakdown needed?

Answer 2

To counterbalance component synthesis, to maintain healthy matrix

Question 3

What can cause an imbalance in turnover of matrix?

Answer 3

• too much synthesis: can cause cause tissue scarring, fibrosis, cancer (via alteration of function)
• too much breakdown: can cause developmental/ induced deficiencies/ breakdown, arthritis/ metastasis (loss of function)

Question 4

What type of enzyme breakdowns proteins?

Answer 4

Proteases (biological scissors)

Question 5

What is the role of proteases?

Answer 5

They degrade (or cleave) other proteins and can be divided into aspartic, threonine, cysteine, serine or metallo

Question 6

Explain the 3 minimal domains that characterised the metalloproteinase family

Answer 6

• 1st is removed during secretion and then to activate
• 2nd is a catalyic domain that binds Zn2+
• 3rd is a substrate specficity domain that targets protein to metabolise

Question 7

Explain the function of the 3 sub families of the metalloproteinase family

Answer 7

1. MMP (matric metalloproteinases): key ECM modifiers
2. ADAM (a disintegrin-like and metalloproteinases): mostly membrane bound
3. ADAMTS (a ADAM with thrombospondin motifs): secreted into ECM and include pro-collagenases& aggregenases which also digest collagen and aggregan

Question 8

What are the functions of the metalloproteinase family members in the ECM?

Answer 8

• ECM modification

- Mediation of ECM componenet breakdown (and release/ activation of growth factors, hormones, cytokines anchored in ECM)

Question 9

What are the key features of the metalloproteinase family members in the ECM?

Answer 9

• Zn 2+ binding catalytic domains
• secretion into ECM as inactive pro-enzyme
• high degree of specificty, recognising specific sequence within ECM components

Question 10

How are family members of metallproteinases activated?

Answer 10

By removal of pro ‘bait’ region by other proteins

Question 11

How are family members of metalloproteinases inhibited?

Answer 11

• by alpha 2 macroglobulin ( present in blood and is ubiquitous proteinase inhibitor)
• tissue inhibitors of metalloproteinases family of small secreted proteins; these slot into active sites of metallo’s catalytic domains

Question 12

What does cleavage of ECM components generate?

Answer 12

• Specific catabolic fragments

- Formation of non-epitopes which have allowed researchers to monitor ECM breakdown in disease

Question 13

What does loading stress produce?

Answer 13

Fragments of ECM comonents, which stimulate increased ECM synthesis and restore hometostatic balance

Question 14

When can ECM synthesis/ breakdown (remodelling) be established?

Answer 14

• embryonic development (cell migration is key and that’s dependent on ECM breakdown and reassembly)
• wound healing (MMPs important
• prevention of tumour development

Question 15

Explain the use of MMPs in wound healing

Answer 15

Damage to matrix induces inflammation which promotes MP/ ECM synthesis
- MMP-1 required for keratinocyte migrate, 7 influences neutrophil migration and release VEGF & TNF alpha allows angiogenesis

Question 16

Explain how MMPs are related to tumour development

Answer 16

• tumour development can be restrained by matrix
• but if other cells become cancer associated they might upregulate their MMPs and start to destroy the matrix
• this allows tumour to leave this site and disseminate, where it can get into bloodstream and mestastasize

Question 17

What molecules are ECM fragments recognised by?

Answer 17

• Integrins expressed by many ECM cells (signalling results in increased ECM synthesis)
• PRR expressed by many ECM cells (signalling results in inflammation via production of IL-1, TNF-alpha, TGF- beta)
  inflammatory cytokines influence ECM synthesis and catabolism

Question 18

Explain an implicatoin of the damage/ fragmentation loop work?

Answer 18

It has the potential to induce more damage and inflammation causing irreversible ECM loss and disease

Question 19

Excessive ECM breakdown can lead to tumour survival/ breakdown. True or false?

Answer 19

True