Ecm Homeostasis Flashcards
What Is homeostasis
Balance between ecm synthesis and breakdown (catabolism)
Is the ecm an inert framework
No consistently broken down and changing
What is ecm homeostasis changes called
Ecm remodelling
How do cells around ecm allow for homeostasis
Secrete ecm products like collagen but also secrete enzymes which break them down
What must cells get before breakdown catabolism occurs
A stimuli
What can too much ecm cause
Fibrosis /scarring or cancer
Eg by excess collagen
What can too much catabolism cause
Osteoarthritis, developmental deficiency , metastasis
What is one stimuli that causes catabolism
Excess pressure
Which type of enzymes cause catabolism
Proteinases (ic and EC)
What are the ic proteinase not to do with ecm breakdown
Enzymes ic which are at low ph
Aspartic,cysteine and threonine proteinases.
Ie the proteasome in ag processing
Which ph do EC proteinases work at for ecm catabolism
Neutral ph
What are the 2 types of EC proteinases
Serine proteinases (cathepsin G)
Or
Metalloproteinases
What is the human degradome
The 570 genes for proteinases eg metalloproteinases
How many genes are there for metalloproteinases
191
How many domains do all metalloproteinases have
3
Pro domain , catalytic domain zn, substrate specificity domain
What is the pro domain for
Removed when secreted outside of cell to activate the metalloproteinases
What does the catalytic domain need
Zinc or metals for catalytic activity
Name the 3 metalloproteinases
MMP (matrix metalloproteinases)
ADAM (a disintegrin like and metalloproteinase)
ADAMTS (ADAM with a thrombospondin motif)
What is the substrate specific domain in mmp which recognise specific sequences on ecm components
Hemopexin/ haemopexin
Give examples of mmp
Collagenases mmp-1
Gelatinases
Matrilysins
Membrane type MT
Are mmp secreted by cell or membrane bound
Secreted unless membrane type MT mmp
What is a disintegrin on adam
Small proteins which block integrin interactions in cell adhesion
What is thrombospondin which makes adamts unique
Adhesion gp which allows cell to cell or cell to matrix interaction
Which metalloproteinases are membrane bound not secreted
Adam
Give 2 examples of adamts
Aggrecanases
Pro collagenases
What substrate specific domain do adam and adamts have
Dis-sp1
What is released due to ecm breakdown
Things bound like gf,hormones and cytokines
What are metalloproteinases secreted as and then how is this stopped
Pro enzymes inactive (except Adam)
Pro bait region removed
Which 2 inhibitors are there for metalloproteinases
A2 macroglobulin (inhibitor in blood)
Timps (tissue inhibitors)
How do timps work
Slot into active site of metalloproteinases
What are neo epitopes
The ecm fragments which are from catabolism eg aggrecanase cuts at specific sites
How is ecm breakdown monitored
Antibody searching for neo epitopes
What do fragments / neo epitopes allow for homeostasis
Allow stimulation of more ecm to be produced in return of catabolism
Why is mmp1 important for wound healing
Allows for keratinocytes migration which produce new epidermal layers
Why is mmp7 important for wound healing
Allows neutrophil migration
Also release of vegf and TNFa for angiogenesis
What can cause abnormal ecm building to promote tumours/cancer
Cross linking of collagen and cancer fibroblast production
This then allows other things like tumour angiogenesis
After metalloproteinases action, how are they stopped
Endocytosed into cell and then lysosome degradation
Which 2 things on cells recognise ecm fragments after catabolism
Integrins
Or
Prr (the fragments are DAMPS)
What does binding to prr by fragments cause
Inflammation via release of cytokines either causing synthesis or Further breakdown
Which 3 cytokines released after prr binding cause synthesis and block breakdown
Tgf b-1
Igf-1
Bfgf
Which 2 cytokines cause further breakdown which causes diseases
Tnf-a and Il-1
Other than tgf b , igf 1 and bfgf what blocks breakdown
Il 6
