BMS2002 - extracellular matrix

Question 1

basal lamina

Answer 1

thin layer/mat of connective tissue comprised of mostly ECM that cells attach to
- essential for maintaining epithelial tissues

Question 2

apical =

Answer 2

cells touching the free surface

Question 3

basal =

Answer 3

cells touching the basal lamina

Question 4

Adherens junction

Answer 4

cell junction where cadherins connect to actin in cytoskeleton

Question 5

cadherin

Answer 5

calcium ion dependent
homophilic binding

Question 6

cadherin domains

Answer 6

• 5 copies of EC domain separated by flexible hinge regions
• calcium binding prevents flexing -> promotes binding to another cadherin
• IC domains interact with actin via catenin and adapter proteins e.g. vinculin

Question 7

Desmosomes

Answer 7

cell junction that uses cadherins that connect to intermediate filaments in cytoskeletal filaments

Question 8

tight junction

Answer 8

epithelial sheet seals two neightboring cells together
- prevents leakage of EC molecules between them
- helps polarize cells
- apical transporters allow selective transport across epithelia

Question 9

gap junction

Answer 9

forms small channels from connexins and innexins
- allow small, water-soluble molecules to pass cell-cell

Question 10

actin-linked cell matrix junction

Answer 10

anchors actin filaments in a cell to ECM

Question 11

hemidesmosome

Answer 11

anchors intermediate filaments in a cell to ECM

Question 12

what is basal lamina composed of?

Answer 12

laminin, collagen type IV, XVIII, nidogen, perlecan, fibronectin

Question 13

indigenous cells in connective tissue

Answer 13

primitive mesenchymal cells
fibroblast
specialised cells

Question 14

immigrant cells in connective tissue

Answer 14

immune cells

Question 15

composition of connective tissue ECM

Answer 15

1. GAGs (glycoaminoglycans)
2. fibrous proteins - collagen family
3. glycoproteins e.g. elastin, fibronectin

Question 16

GAGs

Answer 16

Glycoaminoglycans
- large, highly charged polysaccharides that bind lots of water
- v. anionic
- consist of repeated sulphated disaccharide units
- bind proteoglycans to forms complexes (e.g. aggrecan) that can self-aggregate

Question 17

collagen

Answer 17

• long, stiff, triple strand helical structure
• provides tensile strength
• 3 alpha polypeptides form a coil -> can self aggregate into fibrils and fibres once outside the cell

Question 18

procollagen

Answer 18

prevents collagen aggregation while inside cells

Question 19

Elastins

Answer 19

provide elasticity to connective tissues
- similar structure to collagen
- dominant component of ECM in arteries

Question 20

Fibronectins

Answer 20

• bind other matrix/cell membrane proteins
• organise matric and provide cell-matrix link

Question 21

Integrins

Answer 21

key receptors that allow ECM to interact with cytoskeleton
- provides strength
- used to pull some components through the ECM (need to make and break connections)

Question 22

Talin

Answer 22

important integrins adapter molecules

Question 23

Activating integrins (inteacellular signalling)

Answer 23

thrombonin binds receptor -> Rap1 converts GDP to GTP -> inactive integrin + RIAM + inactive talin + kindlin -> active integrin -> viniculin allows integrin to connect to actin -> provides physical link to cytoskeleton

Question 24

too much matrix synthesis, not enough breakdown ->

Answer 24

alteration of function
- tissue scarring, fibrosis, cancer

Question 25

too much matrix breakdown, not enough synthesis ->

Answer 25

loss of function - developmental/induced deficiencies - arthritis - metastasis

Question 26

what do metalloproteinases need to be active?

Answer 26

Zinc, Zn2+

Question 27

3 families of metalloproteinases?

Answer 27

1. MMP - matrix metalloproteinases e.g. collaginases 2. ADAM - a disentegrin-like metalloproteinases 3. ADAMTS - ADAM with thrombospondin motifs (involved in ECM catabolism)

Question 28

metalloproteinases

Answer 28

key modifiers mediating catabolism of ECM components - release/activation of growth factors, hormones, cytokines - anchored in ECM

Question 29

metalloproteinase characteristics

Answer 29

- Zn2+ binding domain - secretion into ECM as pro-enzymes - activated by removal of pro-region by proteinases

Question 30

metalloproteinase inhibitors

Answer 30

- A2 macroglobulins - TIMPs - tissue inhibitors of metalloproteinases: slot into catalytic domains

Question 31

ECM remodelling (homeostasis)

Answer 31

loading stress -> fragments ECM components -> fragments stimulate ECM synthesis -> restores healthy matrix

Question 32

ECM remodelling is essential during

Answer 32

1. embryonic development 2. wound healing 3. prevention of tumor development - tumour cells held up in matrix -> can't grown and develop

Question 33

3 main types of cartilage

Answer 33

1. Hyaline (articular) 2. fibro 3. elastic

Question 34

components of Hyaline cartilage

Answer 34

- defined by the presence of indigenous chondrocytes - type 2 collagen and aggrecan -> strength and support

Question 35

proteoglycans

Answer 35

- highly charged: can associate lots of water -> hydrated gel - provides resistance to compression - swelling - strength and support

Question 36

Adult stem cells only contain one cell type:

Answer 36

chondrocytes - secrete components that establish cartilage

Question 37

chondrocytes differentiate from...

Answer 37

mesenchymas stem cells (MSC) during embryonic development

Question 38

key signal for cartilage -> bone

Answer 38

Sox9

Question 39

how does bone grow from cartillage

Answer 39

from the centre, forcing caritlage towards the end - inside out

Question 40

control of PTHrP

Answer 40

PTHrP = key skeletal morphogen (hedgehog responsive gene) - IHH and PTHrP in positive feedback loop that maintain spatial chondrocyte proliferation Hedgehog signalling

Question 41

formation of long bones

Answer 41

cartilage is catabolized osteoid ECM becomes calcified -> traps osteoblasts from inside out and then from each end (distal/proximal epiphys)

Question 42

osteoblast ->

Answer 42

osteocyte -> becomes trapped in osteoid responsible for bone homeostasis

Question 43

osteoid

Answer 43

bone ECM

Question 44

osteoclasts

Answer 44

break down newly formed bone -> cavity for bone marrow

Question 45

IHH/PTHrP feedback in long bone formation

Answer 45

PTHrP maintains chondrocyte poliferation and prevents their terminal differentiation As proliferating cells move further from central cells, they recieve less PTHrp This also reduced IHH -> make less PTHrP -> become more osteoblast-like -> contributes to the ossification process

Question 46

cartilage model

Answer 46

embryonic bones - replaced by bone during development

Question 47

Key components broken down in OA

Answer 47

Aggrecan and collagen - more dependent on collagen cleavage than aggregan destruction

Question 48

GDF5

Answer 48

gene involved in OA - growth factor member of TGF-b fam - important in ECM homesotasis

Question 49

RUNX2

Answer 49

gene involved in OA - master transcription factor responsible for driving endochondrial ossification (MMP-13 expression)

Question 50

PTHLH

Answer 50

gene involed in OA - encodes PTHrP chondrocyte growth factor driven by IHH secretion

Question 51

SMAD3

Answer 51

gene involved in OA - intracellular signalling protein involved in TGF-b production - induces ECM synthesis, reduces MMP expression

Question 52

Rheumatoid arthritis is characterised by

Answer 52

inflammation in the synovium