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BMS2002 > L10 > Flashcards

L10 Flashcards

1
Q

what is the ECM

A

is a network of fibrous proteins and hydrated proteoglycans which surround cells in tissues

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2
Q

what are the functions of the ECM

A

provides strength and support

guides cell migration and polarity

permits intercellular communication

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3
Q

what does Maintenance of a healthy ECM depend on

A

balance between synthesis and breakdown of matrix molecules

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4
Q

How is a healthy ECM maintained

A

cells within ECM secrete the components of the ECM

the same cells also secrete enzymes which digest/breakdown these components

to remove damaged matrix
i.e. ‘remodel” matrix

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5
Q

what happens when matrix synthesis is higher than its breakdown

A

tissue scarring, fibrosis, cancer
(alteration of function)

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6
Q

what happens when matrix breakdown is higher than its synthesis

A

developmental/induced deficiencies/breakdown, Arthritis/metastasis
(loss of function)

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7
Q

what are proteinases

A

enzymes that break down proteins

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8
Q

what proteinases are intracellular

A

aspartic proteinases

cysteine proteinases

threonine proteinases

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9
Q

what proteinases are extracellular

A

serine proteinases

metallo-proteinases

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10
Q

what is the degradome

A

570 genes in in the human genome that encode proteinases

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11
Q

what are the domains of metalloproteinase

A

pre

pro

catalytic domain (CD)

substrate specific domain

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12
Q

which domain binds Zn 2+

A

CD

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13
Q

what domains are removed during secretion

A

Pre and Pre

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14
Q

what are the types of metalloproteinase

A
  1. MMP (matrix metalloproteinases)
  2. ADAM (a disintegrin-like and metalloproteinase)
  3. ADAMTS (a ADAM with thrombospondin motifs)
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15
Q

what additional domain do ADAMs have that MMPs don’t

A

disintegrin-like domain

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16
Q

give examples of MMPs

A

collagenases (MMP-1, -8, 13, 18)

gelatinases (MMP-2, -9)

stromelysins (MMP-3 -10, -11

matrilsins (MMP-7, -26)

membrane-type ((MT); MMP-14,-15, -16, -17 -23, -24, -25)

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17
Q

give a feature of ADAM

A

mostly membrane bound

18
Q

give a feature for ADAMTS

A

secreted into ECM like MMPs

19
Q

give examples for ADAMTS

A

pro-collagenases (ADAMTS-2, -3, -14

aggregenases (ADAMTS-1, -4, -5, -8, -9, -15)

20
Q

The metalloproteinase family are involved in ECM breakdown. what is ECM breakdown called

A

catabolism

21
Q

Metalloproteinase family work inside the cell

22
Q

what is the substrate specific domain in MMPs

A

Haemopexin

23
Q

what is the substrate specific domain in ADAM and ADAMTS

24
Q

what do metalloproteinase family members (MMP, ADAM, ADAMTS) mediate

A

breakdown (catabolism) of ECM components and release/activation of growth factors, hormones, cytokines anchored in ECM)

25
Q

what are metalloproteinase family members characterized by

A

Zn2+ binding catalytic domain

secretion into ECM as inactive pro-enzymes

activated by removal of pro “bait” region by other proteinases

26
Q

metalloproteinases are highly specific

27
Q

what are metalloproteinases inhibited by

A

alpha 2 macroglobulin

tissue inhibitors of metalloproteinases (TIMPs)

28
Q

what are the features of alpha 2 macroglobulin

A

found in blood

ubiquitous proteinase inhibitor

29
Q

what are TIMPs

A

small secreted proteins which “slot” into active sites of metalloproteinase catalytic domains

30
Q

what are neo-epitopes

A

epitopes that appear after agricans are cleaved by ADAMTS-4/5 or MMPs

31
Q

what antibody binds to neo-epitopes produced by aggrecanase

32
Q

what antibody binds to neo-epitopes produced by MMP

33
Q

Loading stress also produces fragments of ECM components. what do these fragments stimulate

A

increased ECM synthesis

34
Q

when is ECM re-modelling essential

A

embryonic development

wound healing

prevention of tumour development

35
Q

which MMP is required for keratinocyte migration in wound healing

36
Q

which MMP influences neutrophil migration in wound healing

37
Q

which MMP releases VEGF and TNF-a allows angiogenesis in wound healing

38
Q

how does ECM re-modelling prevent tumor development

A

tumor cells make MMPs

MMPs degrade the basal lamina around tumor cells

tumor cells metastasise and get into the blood for example

39
Q

what are the levels of Controlling metalloproteinase activity

A

gene expression of ECM proteins

localization

maturation

inhibition

degradation

40
Q

how does the Recognition of ECM breakdown products lead to homeostatic control

A

ECM/fragments are recognized by integrins
expressed by many ECM cells. Signaling results in increased ECM synthesis

ECM/fragments are also recognized by PRR
expressed by many ECM cells. Signaling results in inflammation i.e. production of IL-1, TNF-alpha, TGF-beta

41
Q

what inflammatory cytokines are produced during ECM synthesis

A

TGF-beta

IGF-1

bFGF

42
Q

what inflammatory cytokines are produced during ECM breakdown

A

IL-1

TNF-alpha

BMS2002 (21 decks)

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