block III: CT video 2 Flashcards
Which collagens are present in the basement membrane?
Type IV
Type VII
Type III collagen fibrils!!!
Mention the function of type IV collagen in BM?
The major component of the lamina densa of the basal lamina. This is a non-fibril forming collagen
Mention the function of type VII collagen in BM?
Forms thin anchoring fibrils that link lamina densa of basement membrane to underlying lamina reticularis
Mention the function of type III collagen fibrils in BM?
Associated with the reticular layer of
the basement membrane. Made by
CT cells.
identify
EM showing the attachment of the basal lamina to the underlying lamina reticularis collagen fibers by type VII collagen anchoring fibrils and fibrillin microfibrils
identify
What pathologies involve mutations in collagen or its synthesis?
Scurvy, osteogenesis imperfecta and Ehlers-Danlos
What happens in Scurvy syndrome?
Defective synthesis of collagen due to lack of vitamin C and iron as cofactors for hydroxylation of proline and lysine in collagen synthesis.
This results in unstable collagen molecules or in poor crosslinking of the collagen molecules in the collagen fibril
Why does scurvy happen and what are some of the symptoms?
Typically due to a lack of fruits and meat in diet. Characterized by weakness & fatigue, bleeding gums, easy bleeding, poor wound healing, and fragile skin. Still present in under-developed countries where the diet is poor
what happens in osteogenesis imperfecta?
defects in type I collagen characterized by easily fractured brittle bones, abnormal teeth, weak tendons, blue sclera, and progressive hearing loss (defective bones in middle ear).
WHat are some symptoms of osteogenesis imperfecta?
Note that in cases of suspected child
abuse, this disease may need to be considered as it also may present as multiple bone fractures similar to those seen in child abuse (but not related to abuse in this case)
What is the general overview of Elhers danlos syndrome?
are a family of disorders resulting from defects in collagen molecule synthesis. Currently there are at least 13-subtypes. These subtypes vary in severity and whether the defect is in specific collagen protein chains or in the enzymes
involved in the processing of the procollagen chains.
Although these syndromes were initially
named using roman numerals, this has been changed and the various syndromes are classified according to effects
What is classical Ehlers-Danlos syndrome?
is relatively mild and typically results from
defects in collagen type V, although it can also involve defects or mutations in type I
collagen not involving glycine residues in the Type I collagen.
By what is classical Ehlers-Danlos characterized?
Characterized by hyperextensibility of skin & joints, easy bruising of skin, fragile skin, and poor wound healing.
It illustrates that the involvement of type V collagen in formation of type I
collagen fibrils may be important.
What is Vascular Ehlers-Danlos?
one of the most severe and results primarily from defects in collagen type III (reticular fibers).
By what is vascular Ehlers-Danlos characterized?
Characterized by ruptures of walls of major tubes in vascular and gastrointestinal tract.
The vascular effects involving dissection and rupture of the aorta or other large arteries or ruptures in the GI tract often results in early death (~ 50 yrs or younger)
what is the diameter of elastic fibers and its stain?
- typically 1-2 microns in diameter. Frequently branch
- Require special elastic stains to be easily seen. Are not easily visualized just with H&E staining
what is the ability of elastic fibers?
ability to reversibly stretch up to 150% of their length without breaking
What function of elastic fibers is important?
while providing some mechanical
strength are important in adding elasticity in the connective tissue and to that region of the organ
identify
Elastic fibers stained in dermis of skin
identify
Elastic fibers stained in wall of aorta (elastic lamellae)
how does elastic fibers appear in EM?
the elastic fiber appears as an amorphous central area composed of the crossliked elastin molecules with beaded-like
microfibrils composed of the protein
Fibrillin-1 both embedded in it, and
surrounding the surface of the fiber
identify
EM of elastic fiber showing region of elastin and fibrillin 1 containing microfibrils (arrows)
explain the crosslinking of elastic fibers
Within the elastic fiber, individual elastin molecules are crosslinked by unusual ring-shaped amino acids called desmosine and
isodesmosine which crosslink pairs of lysine (or modified lysine) residues present on one elastin monomer to a similar pair of lysine residues on an adjacent elastin molecule
How does lysine in elastin should be?
must be only 2 or 3 amino acids apart in the polypeptide chain. Lysl oxidase required for cross-linking.
why is cross-linking in elastic fibers necessary?
necessary for the elastic properties of the
elastic fiber
identify
how is elastin in unstretched way?
Elastin in the unstretched state takes up a more globular shape or conformation as its lowest free energy state
WHat happens to elastin when it is streched?
When external stretching forces are applied, the molecule can unfold into a
more linear conformation.
Upon removal of these external forces it will return to its original conformation
What does crosslink between elastin molecules allow?
allow change in state (stretch or unstretched) to occur across all the molecules in the fiber giving it its
elasticity
What is the role of fibrillin microfibrils?
form first by a head-to-tail bonding of fibrillin-1 molecules giving a beaded appearing structure;main role formation of elastic fibers
what is MAGP-1 and what does it do?
Microfibril-associated glycoprotein-; binds to fibrillin-1 at the beaded regions, and facilitates the secondary binding of tropoelastin molecules along the microfibrils
WHat does lysyl oxidase crosslinks and what does it do?
Lysyl oxidase crosslinks the tropoelastin molecules by way of the pairs of lysine residues on adjacent tropoelastin molecules which subsequently appear to form the amorphous structure of the elastin
What is Marfan’s syndrome?
(pathologies involving elastic fibers) mutation in the fibrillin-1 gene on chromosome 15. Typically seen in very tall thin individuals who have abnormally long fingers, and lax joints
What are some symtpms and issues of marfan’s syndrome?
- Pulmonary problems due to reduced elastic fibers in lungs
- Dislocations of the lens since the lens suspensory fibers are composed of fibrillin
- Valve defects due to less elastic tissue in valves or its defective elasticity
- Fragile vascular walls which can lead to early death
What characteristic may suggest possibility of marfan’s syndrome?
both the long fingers and frequent dislocations of the lens together
Why do patients with marfan’s syndrome are prone to death by mid 40s?
because of dissection and catastrophic
ruptures in the wall of the aorta
identify
Aorta from individual with Marfan’s syndrome. Note fragmented or absent elastic lamellae in wall
What happens with the aortas of some marfan’s syndrome individuals?
display cystic medial degeneration, a condition in which the fenestrated elastic membranes (lamellae) as well as the smooth muscles of the tunica media of the
aorta are reduced in quantity or are partially absent, and replaced with ground substance
Why does wrinkles and photoaging of skin occur and what is disrupted in this?
Both with age and exposure to sunlight the number of elastic fibers decreases but in addition with photo-aging there is an abnormal increase in diameter and
stiffness of the remaining defective fibers.
This may involve effects of sunlight on fibrillin-1 in the elastic fibers of skin.
This can result in the extreme wrinkled appearance of the skin seen both with age and with exposure to sun light.
What is also related with photoaging and age?
associated decreases in production of type I and type III collagens and faulty collagen fibers due to defects in crosslinking of the collagen
What is the general composition of ground substance?
composed predominantly of glycosaminoglycans (GAGS), proteoglycans, proteoglycan aggregates, and multiadhesive glycoproteins
What are the major GAGS?
- hyaluronic acid (non-sulfated)
- chondroitin 4-sulfate
- chondroitin 6-sulfate
- keratan sulfate
- dermatan sulfate
- heparan sulfate
- heparin
Which GAGS are sulfated?
all except hyaluronic acid
What are GAGS?
linear chains of repeating disaccharide (sugar) units composed of a sugar amine (N-acetylgalactosamine or Nacetylglucoseamine) and a uronic acid sugar such as glucuronate
Where do GAGS bind to?
GAGS (except hyaluronic acid) bind to core proteins to form proteoglycan
monomers
Which monomers bind to hyaluronic acid?
Proteoglycan monomers may in turn then bind to hyaluronic acid by way of link
proteins to form proteoglycan aggregates up to 20 microns long
What are polyanions and what do they bind to and their role?
negatively charge molecules;
GAGS, proteoglycans, & proteoglycan aggregates are polyanions that bind large
amounts of water to form hydrated gels that play a role in filtration of ions and
molecules in extracellular space & resist compression for example in cartilage
What are multi adhesive extracellular glycoproteins and their function?
are multidomain molecules with multiple binding sites for other glycoproteins, collagen, and cell surface molecules.
They act to stabilize the extracellular
matrix and play a role in binding of
cells to it. Some are in basal lamina
and attach epithelial cells to CT
WHat are some of the multi-adhesive extracellular glycoproteins?
- Fibronectin
- Laminin
- Tenascin
- Osteopontin
- Chondronectin
- Osteonecti
