Strand 2 - Extracellular matrix Flashcards
which 3 cell tissue types have a high frequency of cell-cell contact but a low frequency of cell- ECM contact?
epithelial, muscular, nervous
which cell tissue type has a low frequency of cell-cell contact but a high frequency of cell- ECM contact?
connective tissue
how are mechanical forces transmitted from cell to cell in epithelial tissue?
via cytoskeletal filaments (also give strength)
in epithelial tissue, what are the individual cells linked by?
cell junctions
cells in epithelial tissue are asymmetrical or symmetrical?
asymmetrical
cells in epithelial tissues are polarized or non polarized?
polarized
epithelial cells are attached to a thin layer of connective tissue comprising mostly of ECM called the……?
basal lamina
the 4 shapes of epithelial cells are…… (hint: CCSS)
columnar
cuboidal
squamos
stratified
What are the 4 types of cell junctions found in epithelial cells?
adherens junctions
desmosomes
tight junctions
gap junctions
what do adherens junctions hold onto each other via?
cadherin molecules
which 3 subfamilies of cadherins are there?
E, N and P cadherin
is cadherin binding homo or heterophillic?
homophillic - they bind to themselves
Which region of cadherin molecules does Ca2+ bind to?
(flexible) hinge region
what does the binding of Ca2+ prevent on cadherins?
flexing of the hinge regions (promotes homophillic binding of Ca 2+)
which domain does actin interact with on cadherins??
the intracellular domain
how does actin interact with the intracellular domain of cadherins? which two molecules?
via catenins and vinculin
give 3 examples of catenins
alpha catenin
beta catenin
p120 catenin
give an example of an adaptor protein that interacts with actin/domain of cadherins
vinculin
desmosomes contain specialised cadherins that connect with ……. rather than actin filaments (adherens junctions)?
intermediate filaments
tight junctions in epithelial cells act as what?
a selective permeability barrier
name a differential transporter molecule, expressed on the apical and basal plasma membranes, found in the small intestine
glucose (GLUT) transporters
name 2 tight junction proteins
claudin and occludin
gap junctions in epithelial cells are channels/pores made from which 2 molecules?
connexins and innexins
what do gap junctions allow to pass through their pores?
intracellular/water soluble molecules
what does the ECM provide support and strength via? which two structures?
cartilage and the basal lamina
in which 4 processes does the ECM facilitate cell migration and cell shape?
embryonic development
angiogenesis
wound repair
tumour development
what 6 components make up the basal lamina?
laminin
type 4 collagen
type 18 collagen
nidogen
perlecan
fibronectin
cells found in connective tissue are indigenous, including…..
primitive mesenchymal cells
which type of tissue do primitive mesenchymal cells lead to the generation of? give 2 examples of cells which contain this type of tissue
connective tissue
cells such as adipocytes and mast cells
which molecules, found in connective tissues, synthesise most of the molecules found in the ECM?
fibroblasts
name two specialised cell types found in connective tissue
chondrocytes and osteoblasts
which 3 molecules make up the connective tissue ECM?
GAGs
fibrous proteins (collagen)
glycoproteins (elastin)
when connective tissue ECM becomes calcified, which structures can it form? 2 examples
bone and teeth
when connective tissue ECM becomes transparent, what structure can it form?
cornea
which 2 components make up a GAG?
sulphated disaccarides and core proteins
give an example of a small core protein in GAGs
decorin
give an example of a large core protein in GAGs
aggrecan
which molecule can bind up to 1000 GAG molecules? (allowing self aggregation)
hyaluronan
collagen is a ……… stranded helical structure
triple
how many alpha chains make up the helix in collagen?
3
what is the function of procollagen inside cells?
to prevent self aggregation
terminal procollagen extensions are cleaved by which enzyme?
procollagen proteinase
elastins make up most of the ECM in which blood vessel?
arteries
what do fibronectins bind in connective tissue?
intergrins
or other cell membrane/matrix proteins
what are the key receptors that bind ECM components to the cytoskeleton, mainting strength ?
integrins
integrins are made up of what 4 components?
( hint: 2 chains, 2 domains)
alpha chain
beta chain
N terminal domain
intracellular domain
which adaptor molecule connects integrins with the cytoskeleton (e.g actin filaments)?
talin
intergrins exist in which 2 conformations?
active and inactive
cells that migrate through the ECM use integrins to do what?
to pull themselves through the ECM
which kinases do integrins recruit, leading to altered gene expression (ECM homeostasis)?
Focal Adhesion Kinases / FAKs
the human degradome comprised of genes which encode which type of enzyme?
genes which encode proteinases
what are the 5 types of proteinases? (hint: start with amino acids and end in -ase)
aspartic proteinases
cysteine proteinases
threonine proteinases
serine proteinases
metallo proteinases
matrix metalloproteinases (MMPs) are key modifiers of what?
the ECM
name 2 members of the metalloproteinase family (not including MMPs) which are involved in ECM breakdown
ADAM and ADAMTS
what are metalloproteinases characterized by? (hint: a domain)
Zn 2+ binding domain
what are metalloproteinases inhibited by?
alpha-2 macroglobulins and TIMPS
ECM cleavage creates catabolic fragments called what? which have allowed researchers to monitor ECM breakdown in disease
neo epitopes
damage to the matrix induces inflammation which promotes ECM synthesis necessary for …… repair
wound repair
what type of immune molecule influences both ECM synthesis and catabolism?
inflammatory cytokines
what are the 3 main types of cartilage?
hyaline, fibro, elastic
where on the body is hyaline cartilage found?
ribs
nose
larynx
trachea
articular joints
where is fibro cartilage found? (hint: within articular joints)
joint capsules, ligaments
where is elastic cartilage found? (hint: think sound and swallowing)
ear, epiglottis, larynx
hyaline cartilage is a precursor for what structure in the body?
bone
what are the 2 key components found in articular cartilage? (hint: needed for strength)
type 2 collagen and aggrecan
what is is Ehlers - Danlos syndrome a defect in, with regards to cartilage, and what does it result in ?
a defect in the deposition of collagen
results in hyperextensible joints
Aggrecan complexes are highly charged due to what?
GAG content
the hydrated gel (due to proteoglycans being highly charged) in cartilage attracts…… which does what?
attracts water
results in turgor / provides strength / provides resistance to compression
what do chondrocytes in adult cartilage secrete?
and what are chondrocytes rich in (2 cellular structures)?
type 2 collagen and aggrecan
rich in RER and golgi
what key transcriptional factor do chondrocytes have?
expression of sox-9
when does chondrocyte proliferation begin?
embryonic development
what 4 things does chondrocyte proliferation require?
TGF - beta
FGF (fibroblast growth factor)
IGF-1 (insulin like growth factor)
PTHrP (parathyroid hormone related protein)
In endochondrial ossification what is replaced by bone during foetal developement?
“cartilage model” is replaced
spatial patterning of chondrocytes during bone formation is facilitated by which group of molecules?
morphogens
via which type of signalling do morphogens spatially pattern chondrocytes during bone formation?
via inductive signalling
Which members of the hedgehog family of proteins control production of the morphogen PTHrP?
SHH, DHH, IHH
Which two molecules interact via positive feedback loops to maintain spatial chondrocyte proliferation?
(Hint: a member of the hedgehog family and a morphogen)
IHH and PTHrP
In drosophila, hedgehog interacts with a)…….. and b)……… to keep the proteolytic processing of c)……. turned off
a) Patched
b) smoothened
c) Cubitus Interruptus (Ci)
what 2 things does osteoid ECM contain?
hydroxyapatite and collagen
cartilage is catabolized during the formation of bone in embryonic development. What happens next?
Cartilage becomes calcified
Osteoblasts get trapped
Which molecule maintains chondrocyte proliferation, cartilage production and prevents their terminal differentiation?
PTHrP
As cells move further away from the central ossification centres in bone formation what do they recieve less of?
What does this reduce?
PTHrP
IHH and therefore less PTHrP, becoming more osteoblast like
give 2 examples of articulated joints
hip and knee
define osteoarthritis
slow, progressive loss of ECM
what is the chondrogenic phenotype of osteoarthritis?
mechanical damage without obvious cause (primary OA)
what does osteoarthritis result in clinically?
limited joint movement, joint deformity, inflammation, severe pain
in cartilage, what are microfilaments of the cytoskeleton attached to ?
integrins
what are integrins attached to in cartilage?
collagen fibres
in cartilage, which complexes are the cartilage fibres attached to?
proteogylcan complexes (polysaccaride + proteoglycan)
what does DMM stand for in osteoarthritis?
destabilisation of the medial meniscus
Does osteoarthritis depend more on collagen cleavage or aggrecan destruction?
collagen cleavage
give an example of a collagenase
MMP-13
Is osteoarthritis monogenic or polygenic?
polygenic
which growth factor family is GDF-5 from? what is it involved in?
growth factor member of TGF-beta family
involved in ECM homeostasis
Where is RUNX2 located on chromosomes and what is it a transcription factor for?
6p 21.1
txn factor for endochondrial ossification - MMP-13
Where is PTHLH located on the chromosomes? What does it encode?
12p 11.22
PTHrP
SMAD3 is an intracellular signalling protein involved in ……. secretion and reducing the secretion of the collegenase called…..
TGF beta
MMP-13
what is MMP-13 inhibited by?
TIMP-3
name two current therapies for osteoarthritis
surgery and NSAIDs
Rheumatoid arthritis is the progressive loss of the ECM in articular cartilage due to what?
immune cell mediated damage (rheumatoid arthritis is an autoimmune disease)
rheumatoid factor, found in the blood of many patients, is classed as an auto…..
auto antibody
rheumatoid is an IgM that bind which other Ig?
IgG
rheumatoid arthritis patients have nuclear antigen molecules react with epitopes that contain………. amino acids
citrullinated amino acids
what is a citrullinated amino acid?
arginine becomes a citrulline
is rhemuatoid factor found in the blood of people who DON’T have rheumatoid arthritis?
yes
some epithelial cancers have been known to downregulate which type of cadherin?
E
