BMS2002 - extracellular matrix Flashcards
basal lamina
thin layer/mat of connective tissue comprised of mostly ECM that cells attach to
- essential for maintaining epithelial tissues
apical =
cells touching the free surface
basal =
cells touching the basal lamina
Adherens junction
cell junction where cadherins connect to actin in cytoskeleton
cadherin
calcium ion dependent
homophilic binding
cadherin domains
- 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
Desmosomes
cell junction that uses cadherins that connect to intermediate filaments in cytoskeletal filaments
tight junction
epithelial sheet seals two neightboring cells together
- prevents leakage of EC molecules between them
- helps polarize cells
- apical transporters allow selective transport across epithelia
gap junction
forms small channels from connexins and innexins
- allow small, water-soluble molecules to pass cell-cell
actin-linked cell matrix junction
anchors actin filaments in a cell to ECM
hemidesmosome
anchors intermediate filaments in a cell to ECM
what is basal lamina composed of?
laminin, collagen type IV, XVIII, nidogen, perlecan, fibronectin
indigenous cells in connective tissue
primitive mesenchymal cells
fibroblast
specialised cells
immigrant cells in connective tissue
immune cells
composition of connective tissue ECM
- GAGs (glycoaminoglycans)
- fibrous proteins - collagen family
- glycoproteins e.g. elastin, fibronectin
GAGs
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
collagen
- 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
procollagen
prevents collagen aggregation while inside cells
Elastins
provide elasticity to connective tissues
- similar structure to collagen
- dominant component of ECM in arteries
Fibronectins
- bind other matrix/cell membrane proteins
- organise matric and provide cell-matrix link
Integrins
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)
Talin
important integrins adapter molecules
Activating integrins (inteacellular signalling)
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
too much matrix synthesis, not enough breakdown ->
alteration of function
- tissue scarring, fibrosis, cancer
too much matrix breakdown, not enough synthesis ->
loss of function
- developmental/induced deficiencies
- arthritis
- metastasis
what do metalloproteinases need to be active?
Zinc, Zn2+
3 families of metalloproteinases?
- MMP - matrix metalloproteinases e.g. collaginases
- ADAM - a disentegrin-like metalloproteinases
- ADAMTS - ADAM with thrombospondin motifs (involved in ECM catabolism)
metalloproteinases
key modifiers mediating catabolism of ECM components
- release/activation of growth factors, hormones, cytokines
- anchored in ECM
metalloproteinase characteristics
- Zn2+ binding domain
- secretion into ECM as pro-enzymes
- activated by removal of pro-region by proteinases
metalloproteinase inhibitors
- A2 macroglobulins
- TIMPs - tissue inhibitors of metalloproteinases: slot into catalytic domains
ECM remodelling (homeostasis)
loading stress -> fragments ECM components -> fragments stimulate ECM synthesis -> restores healthy matrix
ECM remodelling is essential during
- embryonic development
- wound healing
- prevention of tumor development - tumour cells held up in matrix -> can’t grown and develop
3 main types of cartilage
- Hyaline (articular)
- fibro
- elastic
components of Hyaline cartilage
- defined by the presence of indigenous chondrocytes
- type 2 collagen and aggrecan -> strength and support
proteoglycans
- highly charged: can associate lots of water -> hydrated gel
- provides resistance to compression - swelling
- strength and support
Adult stem cells only contain one cell type:
chondrocytes
- secrete components that establish cartilage
chondrocytes differentiate from…
mesenchymas stem cells (MSC) during embryonic development
key signal for cartilage -> bone
Sox9
how does bone grow from cartillage
from the centre, forcing caritlage towards the end - inside out
control of PTHrP
PTHrP = key skeletal morphogen (hedgehog responsive gene)
- IHH and PTHrP in positive feedback loop that maintain spatial chondrocyte proliferation
Hedgehog signalling
formation of long bones
cartilage is catabolized
osteoid ECM becomes calcified -> traps osteoblasts
from inside out and then from each end (distal/proximal epiphys)
osteoblast ->
osteocyte -> becomes trapped in osteoid
responsible for bone homeostasis
osteoid
bone ECM
osteoclasts
break down newly formed bone -> cavity for bone marrow
IHH/PTHrP feedback in long bone formation
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
cartilage model
embryonic bones - replaced by bone during development
Key components broken down in OA
Aggrecan and collagen
- more dependent on collagen cleavage than aggregan destruction
GDF5
gene involved in OA
- growth factor member of TGF-b fam
- important in ECM homesotasis
RUNX2
gene involved in OA
- master transcription factor responsible for driving endochondrial ossification (MMP-13 expression)
PTHLH
gene involed in OA
- encodes PTHrP chondrocyte growth factor driven by IHH secretion
SMAD3
gene involved in OA
- intracellular signalling protein involved in TGF-b production
- induces ECM synthesis, reduces MMP expression
Rheumatoid arthritis is characterised by
inflammation in the synovium
