Extracellular matrix (complete) Flashcards
What is the extracellular matrix
The interstitial fluid that contains ions, proteins, proteoglycans, and signaling molecules
What are the two main components of the extracellular matrix
proteins and proteoglycans
What are the three main proteins in the extracellular matrix
- collagen
- fibronectin
- elastin
What are the five main proteoglycans found in the extracellular matrix
- hyaluronic Acid
- Chondroitin sulfate
- Dermatan sulfate
- Heparan sulfate
- Keratan sulfate
What are the four main functions of the proteins and proteoglycans of the extracellular matrix
- provide shape and structure to the interstitial space
- lubrication and cushioning of cells and other things
- provides an anchor point for cellular adhesion
- allows communication between cells
- controls cell life cyles (proliferation, differentiation, apoptosis, migration, etc)
What do the proteins of the Extracellular matrix provide
Structure and allow cellular adhesion
Do proteins or proteoglycans prevent compression of the ECM (extracellular matrix)
Proteoglycans
what is the major protein of the ECM
collagen
What are proteoglycans
highly charged protein/saccharide polymers that are 95% carbohydrates
What is the specific structure of collagen
- forms a left-handed helix
- 3 amino acids per turn
- each turn has the sequence Gly-X-Y
- Three helical collagen proteins come together to make a triple stranded, right handed superhelix
What type of helix does a strand of collagen form
a left handed helix
how many amino acids per turn are there in collagen
3
what is the specific sequence of amino acids that is found in collagen
Gly-X-Y
X = proline (usually)
Y = hydroxyproline (usually)
What is the quaternary structure of collagen
a triple-stranded right handed superhelix
Where are the glycine residues of a collagen strand located in the triple helix
toward the center of the triple helix
why are the glycine residues of a collagen strand situated toward the center of the triple helix
because of their very small side chain
Why are proline and hydroxyproline used with glycine in a collagen strand
they provide strength to the collagen structure due to their bulk and rigidity
What are the two classes of collagen
fibrillar (fibril-forming) and nonfibrillar
What is the most common type of collagen in the body
Type 1
Can collagen fibers be a mixture of collagen types
yes
What is the main function of fibrillar collagen
provide tensile strength to skin, tendons, and ligaments
What are three types of nonfibrillar collagen
- basement membrane collagen (type 4)
- fibril-associated collagens with interrupted triple helices (FACITs)
- Multiplexins
What happens when nonfibrillar collagen interacts with fibrillar collagen
they produce network, or mesh like structures
What type of collagen is the primary structure of the basement membrane
type 4 collagen
What is the main function of the basement membrane
to prevent migration of certain cell types between different tissue types
What are the steps of collagen synthesis
- Preprocollagen is synthesized with a signal sequence and is directed to the lumen of the ER
- Signal sequence is removed to make Procollagen
- Post translational modifications occur
- proline –> hydroxyproline
- sugars are attached to the protein
- Disulfide linkages are incorporated
- Disulfide linkages trigger formation of triple helical structure
- tropocollagen then moves to the golgi and is exocytosed
- tropocollagen is converted into mature collagen
- mature collagen can be crosslinked to form insoluble collagen fibrils
What occurs in converting preprocollagen into procollagen
the signal sequence is removed
what post-translational modifications are made to precollagen
- prolines are converted to hydroxyprolines
- sugars are attached to the protein
- disulfide linkages are incorporated
What is scurvy
a defect in collagen synthesis that is caused by insufficient vitamin C
How does low vitamin C lead to defective collagen synthesis
Vitamin C is a cofactor for the enzymes that produce hydroxyproline, without vitamin C hydroxyproline isn’t made
What are the symptoms of Scurvy
- Subcutaneous hemorrhages
- muscle weakness
- soft, swollen, and bleeding gums
- osteoporosis
- poor wound healing
- anemia
What is Osteogenesis imperfecta
a defect in collagen synthesis that causes brittle bones
What causes Osteogenesis imperfecta
it is caused by a genetic defect in the genes coding for alpha 1 or alpha 2 collagen chains
Osteogenesis imperfectia is caused by a point mutation in the gene that causes a different amino acid to be in the spots that are usually glycine in collagen. Why is that problematic
because the amino acid replacing glycine will usually have a bulky side chain. which wouldn’t allow the collagen to coil and form the triple helical structure
What are the symptoms of Osteogenesis imperfecta
- fragile bones
- thin skin
- abnormal teeth
- weak tendons
What is the primary function of elastin
it is responsible for the elastic (stretchy) nature of blood vessels, lungs, ligaments, and skin
What is the structure of elastin
a single protein with very little post translational modifications
What is a desmosine
a complex two dimensional lattice work formed by crosslinked elastin monomers
What does the formation of a desmosine (from elastin monomers) permit these elastin fibers to do
it permits the elastin polymers to stretch in two directions
What does fibronectin do in the ECM
it acts as an attachment point for other cellular and ECM components
Is there only one form of fibronectin, or are there multiple, tissue and developmental stage specific
there are multiple tissue and developmental stage specific types of fibronectin
What is fibronectin involved in
cell adhesion
cell migration
embryonic morphogenesis
cytoskeletal and ECM organization
What do proteoglycans form in the ECM
they are the gel-forming portion of the ECM, sometimes called the ground substance
What are proteoglycans? what is their structure
they are protein chains with large amounts of carbohydrates attached
about what percentage of proteoglycans are carbohydrates and proteins
they are 95% carbs, 5% proteins
What do you call the carbohydrate portion of proteoglycans
Glycosaminoglycans (GAGs)
What are the 5 major proteoglycans in the ECM
- Hyaluronic Acid
- Chondroitin sulfate
- dermatan sulfate
- heparan sulfate
- keratan sulfate
Where are proteoglycans primarily constructed
in the Golgi
- Protein portion is delivered from the ER
- the Carb portion is added in the golgi
Where are proteoglycans degraded
in the lysosome
are proteoglycans degraded in a specific sequence, or just randomly
they are degraded in a specific sequence
What occurs if the process of constructing or degrading proteoglycans is disrupted
it leads to a broad class of diseases called Mucopolysaccharidosis
What are lysosomal storage diseases
defects in the lysosomes ability to break down proteoglycans
What is the main function of proteoglycans
to provide structural support to tissues, especially cartilage and connective tissue
What is the effect that proteoglycans have on compression stress
they are largely responsible for preventing compression stress
what makes proteoglycans effective at reducing compression stress
their large negative charges
What are aggrecans
large macromolecular bottle-brush like structures formed by many different proteoglycans interacting with each other
What is the typical overall charge of proteoglycans
its a large negative charge
how do proteoglycans neutralize their large negative charge
by binding numerous counter ions (cations)
What does the high charge density on proteoglycans cause to happen in the ECM
the high charge density of proteoglycans leads to an influx of water into the ECM
What results from the influx of water into the ECM by proteoglycans
stiffness and swelling of the ECM due to the balancing of osmotic forces
What are the properties of the ECM that are directly caused by the highly charged proteoglycans
- Rigidity of the ECM
- Flexibility of the ECM
- Compressibility of the ECM
What does the rigidity, flexibility and compressibility of the ECM allow tissues to do
withstand torsion and shock
What is Hyaluronic Acid
a GAG on proteoglycans
What are the characteristics of hyaluronic acid
- longest chain of the GAGs
- only GAG with no protein core
- only GAG with no sulfonation
- major component of synovial fluid and vitreous humor
- found in ECM of cartilage and skin
What is the function of hyaluronic acid in synovial fluid and vitreous humor
to increase the viscosity
it is one of the major lubricating components
What is the function of hyaluronic acid in the cartilage and skin
- involved in inflammation and wound repair
2. UVB sunburns = decreased hyaluronic acid = inflammation and erythemia
Which GAG doesn’t have a protein core
Hyaluronic acid
which GAG doesn’t have sulfonation
hyaluronic acid
Which GAG is the most common GAG
Chondroitin sulfate
In which tissue is Chondroitin sulfate the major component
cartilage
What is the function of chondroitin sulfate in cartilage
it resists compression of cartilage
What happens in the joints when there is a decrease in chondroitin sulfate
osteoarthritis
Which proteoglycan has the highest charge density
Dermatan sulfate
Which two proteoglycans are structurally similar
Dermatan sulfate and Chondroitin sulfate
What are two disorders associated with disruption of Dermatan sulfate synthesis
- Maroteaux-Lamy syndrome (polydystrophic Dwarfism)
2. Hurler’s syndrome
What is Maroteaux-Lamy syndrone
polydystrophic dwarfism
What is hurlers syndrome
a defect in catabolism of dermatan sulfate
Which of the proteoglycans is the most highly charged of all proteoglycans
heparan sulfate
What is the proteoglycans that is the major component of basement membranes
Heparan sulfate
how is heparin related to heparan sulfate
it is structurally similar, just smaller
What does heparin do
binds to antithrombin III and inhibits the clotting cascade
Which is the most heterogeneous GAG
Keratan sulfate
What are the three different classes of Keratan sulfate
KS-1 Found in the cornea of the eye
KS-2 found in skeletal tissue (bone and cartilage)
KS-3 found primarily in the brain
What causes the differences between the three classes of keratan sulfate
the amino acid of protein attachment
What Amino acids are each of the three classes of Keratan sulfate bound to
KS-1 Asparganine
KS-2 Serine or Threonine
KS-3 Serine of Threonine
How is the ECM like reinforced concrete
the collagen is like the rebar providing strength and support
the proteoglycans act like cement to tie everything together and provide rigidity
Is the ECM a static environment
no, it is constantly being remodeled
why is the ECM constantly being remodeled
to accommodate cell growth, proliferation, and movement
What is responsible for digesting the structural components of the ECM
Matrix Metalloproteases (MMPs)
Are MMPs always active
no they are synthesized as zymogens, and later activated
what are the two types of MMPs
secreted or membrane bound
What can MMPs degrade
collagen elastin fibronectin the protein core of proteoglycans other MMPs
What is different about metaloproteases
they rely on a metal cofactor for activity
What is the metal that MMPs require as a cofactor
ZINC
What happens to activity of MMPs with introduction of a powerful metal chelator like EDTA
the activity of MMPs is abolished
What are the three domains of MMPs
- Propeptide domain
- Catalytic domain
- Haemopexin-like C-terminal domain
What does the catalytic domain do in MMPs
binds the zinc and allows for proteolytic activity
Which of the three domains of MMPs is occasionally absent
the Haemopexin-like C-terminal domain
What is the use of the propeptide domain of the MMPs
while it is attached to the MMP, the MMP is inactive. When the propeptide domain is removed the MMP becomes active
What is the part of the propeptide domain that keeps the MMP inactivated
the cysteine switch
how does the cysteine switch on the propeptide domain keep MMPs inactive while the MMP still have the propeptide domain
the cysteine switch binds the zinc atom and prevents its use by the enzyme.
What does the catalytic domain of MMPs use the Zinc it binds to for
it uses the zinc to activate a water molecule, the water molecule is then able to react with the amide bond of a protein substrate
What are the different classifications of MMPs
- Collagenases
- Gelatinases
- Metalloelastases
- Stromelysins
- Matrilysins
What does collagenases degrade
fibrillar collagen (only mammalian enzyme that can)
what do gelatinases degrade
non-fibrillar collagen
What do metalloelastases degrade
elastin
what do stromelysins degrade
Most ECM proteins, except fibrillar collagen
what do matrilysins degrade
mose ECM proteins except collagen
Can most MMPs activate other MMPs
yes
What is enamelysin
an MMP that degrades amelogenin
What is amelogenin (degraded by enamelysin)
a major component of tooth enamel
What disease is related to defects in enamelysin
Amelogenesis imperfecta
What are the symptoms of amelogenesis imperfecta
tooth enamel is thin, weak, and discolored
they are more susceptible to cavities, and more sensitive to temperature
what are the three proteins that are important in ECM signaling events of MMPs
Integrin receptors
Cytokines
Growth factors
What are integrins
cell surface receptors that link the ECM to the cytoskeleton
what leads to activation of the integrin receptor
A deformation in the ECM
What can the integrin do once it is activated
- transmit the deformation of the ECM to the cytoskeleton (can affect cellular structure)
- Activate cellular transcription factors, modifying gene expression
- it can also transmit information out to the ECM
What is the structure of integrin
dimer with alpha and beta subunits
What things can bind to integrins and what do they do
cations (Ca or Mg)
they are thought to stabilize the ECM binding to the receptor
What two signaling mechanisms can mediate changes in electrical potential
- stretch activated ion channels
2. environmental electrical potentials
What activates stretch activated ion channels
deformation of the cell membrane
What does ion flow into the cell cause
- it can activate intracellular secondary signaling mechanisms, which can lead to transcriptional events
- it can lead to voltage sensitive signaling events through gap junctions
What do gap junctions allow to pass between the cytosol of two adjacent cells
ions and small molecules. when ions flow into one cell they can directly pass to another through gap junctions
what structures make up gap junctions
connexons
Besides integrins, what are three other classes of signaling molecules for the ECM
- cytokines
- Growth factors
- specific ECM modulators
what are cytokines generally thought to be involved in
inflammatory processes
What are the two common classes of cytokines
interleukins (IL)
interferons (IF)
can cytokines signal cells to secrete MMPs
yes
What affect can growth factors have on cells
- cell growth
- cell proliferation
- cell differentiation
are growth factors and cytokines easily distinguishable
no
How are growth factors used in dentistry
a bone growth factor has began being placed in implants to promote bone growth
What are the two parts of bone ECM
- calcified bone matrix
2. Osteoid
Which part of the bone ECM is mineralized (mostly inorganic)
the calcified bone matrix
What cell types are found in the calcified bone matrix
only osteocytes
Which part of the bone ECM is nonmineralized
the osteoid
What happens to the osteoid when it is fully matured
it may become calcified bone matrix
What is the primary substance in the osteoid
type 1 collagen
What is the function of osteoblasts
to build new bone matrix
what is the function of osteoclasts
to breakdown existing bone
What is the function of osteocytes
transmit signals to osteoclasts and blasts to initiate bone remodeling
in normal bone how does osteoclast and osteoblast activity compare
they are balanced
what can cause an imbalance in osteoclast and osteoblast activity
outside stimulus on the bone
orthodontics)(osteoporosis
What attaches the tooth to the alveolar bone
the Periodontal ligament (PDL)
what is the primary cell type in the PDL
fibroblasts
what is the function of fibroblasts in the PDL
to create an intricate collagen structure to secure the tooth to the bone
What happens when the PDL is put under tensile stress
- it releases IL-1, IL-6, and VEGF
- ILs activate MMPs and inactivate TIMP (MMP inhibitor)
- VEGF stimulates angiogenesis
- MMPs degrade ECM to facilitate cell proliferation and capillary growth
- PDL cells and osteoblasts proliferate and grow more bone
What happens when the PDL is compressed
- PDL releases IL1 and 6
- ILs stimulate release of RANKL and MMPS
- MMPs degrade non mineralized surface of osteoid and the ECM
- RANKL stimulates maturation of osteoclasts
- osteoclasts break down bone
