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111 Cards in this Set

  • Front
  • Back
What is an Extracellular Matrix?
A complex of non-living macromolecules manufactured by tissue cells and exported into the extracellular space.
2 constituents of ECM:
-Ground substance
-Embedded fibers
Function of ground substance:
Resists forces of compression
Function of Embedded fibers:
Withstands tensile forces
2 Components of Ground Substance:
1. GAGs
2. Proteoglycans
Unbranched polysaccharide chains of repeating disaccharide units.
A core protein linked to many GAGs
2 types of Fibers embedded in the ECM:
Family of proteins made of a triple helix of alpha helices.
Elastic fibers are made of:
Crosslinked elastin molecules
What coats elastic fibers?
How are cells linked to the ECM?
Via adhesive glycoproteins and integrins
What adhesive glycoproteins are found in ECM?
Basal Lamina
Felt-like cell rug excreted by epithelial and muscle cells
Define "Ground Substance"
An amorphous gel-like material made of GAGs and proteoglycans
What are the common sugars in the disaccharide repeats in GAGs?
1. N-acetylglucosamine or
One of above linked to:
2. Glucuronic or Iduronic acid
General chemical nature of GAGs:
Negatively charged - b/c amino sugars typically are sulfated and have carboxyl groups attached to them.
Result of GAGs being negatively charged:
Na+ binds and osmotially attracts water into the matrix.
Functional role of GAGs:
Serve as a porous, hydrated, gel-like cushion to absorb and disperse compressive loads
4 Main types of GAGs:
1. Hyaluronate
2. Chondroitin/dermatan SO4
3. Heparan sulfate / heparin
4. Keratan sulfate
Function of Hyaluronate
Predominant GAG in loose supporting tissues
How is Hyaluronate different from other GAGs?
-Single disacch unit in long chains of 300-25,000 units
-No covalent bonds w/ proteins
What are Proteoglycans?
A core protein with covalently bound GAGs other than hyaluronate
Where does attachment of GAGs to core protein occur?
In golgi
What is an Aggregan proteoglycan?
Lg multimeric complex of many proteoglycans bound via link proteins to hyaluronate backbone.
Where are Aggregan proteoglycans found?
-Connective tissue
What is the predominant Function of Proteoglycans?
-Molecular filters - screen & retard macromolecules passing through them.
Where is Heparan sulfate proteoglycan found?
In the renal glomerular basal lamina - acting as a molecular filter.
Other than filtering, how do proteoglycans function?
Contain binding sites for
-secreted growth factors (FGF and TGFbeta)
-Protease inhibitors
What is the effect of ligands binding to GF and enzyme receptors on proteoglycans?
Either inhibition or enhancement of the ligands' functions by preventing from reaching destination, or concentrating in spcf area.
What is Syndecan?
A proteoglycan that remains attached to a cell membrane instead of being secreted into ECM.
What allows Syndecan to remain attached to the cell membrane?
The core protein serves as the transmembrane protein.
What does the core protein transmemb component attach to?
-Actin filaments of the cytoskeleton
-Collagen/fibronectin of ECM
How do Syndecans function in fibroblasts?
Bind FGF and present it to the cell membrane's FGF receptors.
Why is it good for Syndecan to present FGF to its receptor?
B/c it concentrates FGF at the membrane.
What is the Proteoglycan genetic disease?
Progeria syndrome
What is Progeria syndrome?
A fatal premature aging disorder
What is the pathology in Progeria syndrome?
Galactosyltransferase in fibroblasts is thermolabile and Dermatan SO4 chains fail to attach to proteoglycan.
What makes up the ECM in addition to proteoglycans? What is it in ECM for?
Fibers - to provide tensile strength and elasticity.
What is the predominant fiber in ECM?
What else is Collagen a predominant component of?
The total mammalian protein mass - it takes up 25%
Where are collagens made?
Connective tissue Fibroblasts synthesize and secrete collagens.
What is the form of collagen when fibroblasts secrete it?
Tropocollagen - a triple helix of 3 alpha helices.
What is the primary AA sequence of Collagen like?
X = commonly proline
Y = commonly hydroxyproline
What happens to Tropocollagen once it gets secreted?
Polymerizes into collagen
How many types of collagen are there?
How many do we need to know?
What is the predominant type of collagen? How much?
Type I - 90% of collagens
What are the 3 different groups of Collagen?
-Fibril forming
-Fibril associated
-Network forming
Which collagens are Fibril forming?
So the polymerized form of the fibril forming collagens is?
What are the Fibril-associated collagens?
9, 12
What is the polymerized form of fibril-associated collagens?
Lateral association
In what tissues are Collagens 9 and 12 found?
9 = Cartilage
12 = Tendon/ligaments
Which collagens are Network-forming?
4, 7
What is the polymerized form of Collagen type 4? Where is it distributed?
Sheetlike network found in basal laminae
What is the polymerized form of Collagen type 7? Where is it distributed?
Anchoring fibrils found in skin.
In what organelle of fibroblasts is collagen made?
Rough ER
In what form is the product of RER during collagen synthesis?
What is it like?
Preprocollagen - alpha helixes that still have their N/C terminals
What does Preprocollagen undergo?
Hydroxylation and glycosylation of Lys and Pro residues
What happens after glycosylation/hydrolyxation of Preprocollagen?
Alignment and assembly into the procollagen triple helix
What happens after Procollagen is made?
-Vesicular secretion to the cell surface via the golgi
What is the first thing that happens to procollagen after secretion?
-Cleavage of propeptides
Product of propeptide cleavage from procollagen:
What happens to Tropocollagen?
Spontaneous assembly in head-to-tail fashion to make collagen fibrils like 1/2/3/7
What stabilizes the collagen fibril structure?
Covalent bonding of neighboring lysine and hydroxylysine residues.
What happens to collagen fibrils?
They aggregate into collagen fibers
What helps formation of collagen fibers?
Fibril-associated Collagens type 9 and 12
What characteristics of collagen fibrils are regulated by fibroblasts?
-Size (length/diameter)
How are collagen fibrils oriented? How is it achieved?
-Along the axis of tension
-Fibroblast cytoskeletons are aligned along it, and orient vesicle secretion that way.
What are 2 nongenetic diseases associated with collagen?
1. Scurvy
2. Keloid
What is Scurvy?
Vit C deficiency that prevents hydroxylation of Pro and Lys residues - decreased stability of collagens.
Symptoms of Scurvy:
-Fragile blood vessels
-Poor wound healing
-Loose teeth in sockets
What is Keloid?
Excessive accumulation of collagen during wound healing
Symptom of Keloid
Elevated scar
4 Genetic Collagen Diseases:
1. Osteogenesis imperfecta
2. Chondrodysplasia
3. Ehlers danlos
4. Defective Type VII collagen
Osteogenesis imperfecta:
-collagen type
Type I
Easily fractured bones
-collagen type
Type II
Cartilage joint deformities
-collagen type
Type III
Weak skin, fragile vessels,
Hypermobility of Joints
Defective type VII collagen:
-collagen type
Type VII
Blistering skin
Dystrophic necrosis of skeletal muscle
What fibers OTHER than collagen are found in ECM?
In what 3 tissues is Elastic fiber particularly important?
-Blood vessels
What proteins compose elastic fibers? (2)
What are Elastin chains like structurally?
-Rich in gly/lys/proline
-Covalently linked by Lys residues
Where is Elastin made?
In fibroblasts
What do elastic fibers consist of?
Elastin center surrounded by the glycoprotein FIBRILLIN.
What syndrome is the result of mutations in Fibrillin gene?
What is the symptom of Marfan's?
Ruptured aneurysms at the aortic root - due to lack of elasticity.
What are the Adhesive glycoproteins in the ECM? What is their function?
Fibronectin + Laminin
-Bound to ECM via specific binding sites on them, they link the ECM to cells
What are integrins?
Transmembrane proteins that serve as cell "receptors" for the ECM - by binding integrin/laminin.
What are integrins composed of?
Heterodimers - a + B subunits
What end of integrins is linked to the ECM?
Amino end
What is the carboxyl end of integrins bound to?
Actin filaments in the cytoskeleton
What are the Integrins that bind fibronectin and laminin called?
Fibronectin or Laminin receptors.
What is the structure of Fibronectin like?
-Lg heterodimer glycoprotein with Disulfide linkages
-Binding sites for collagin, heparin, and integrins.
What is the sequence of the cell-binding site on Fibronectin? What binds to this site?
RGD - ARg/Gly/Asp
-Integrin on the cell is what binds to this site on Fibronectin to connect the cell to ECM.
Where is laminin important?
In linking the basal lamina to cell membranes.
What is the Basal lamina?
A sheetlike network of ECM proteins that interfaces epithelia and nearby CT.
What 4 things compose the basal lamina?
1. Type IV Collagen
2. Perlecan heparan sulfate
3. Laminin
4. Entactin
What are the 3 main functions of the basal lamina?
1. Molecular filter
2. Selective barrier to cells
3. Scaffold for regeneration
What is a good example of how the basement membrane acts as a molecular filter?
At the glomerular filter where the predominant proteoglycan is Heparan sulfate
How does the basal lamina serve as a scaffold for regeneration?
Skeletal muscle myoblasts migrate along BM to orchestrate myofiber regeneration.
To what is BM tethered on its:
-ECM side
-Cell side
ECM side: fibrillar collagens (type VII)
Cell side: integrins via laminin
What cells can't penetrate basal lamina?
-Endothelial cells
What cells can penetrate the basal lamina?
-Nerve fibers
How do cells penetrate the BM?
Via release of collagenases and serine proteases
What enzyme is essential in degrading BM for cell traversal?
What 2 molecules are the regulators of matrix degradation?
tissue inhibitor of metalloproteinase
Serine protease inhibitor
What happens when skin epithelial cells break through the BM?
Tissue metastasis of malignant melanoma cells.
When do endothelial cells penetrate the ECM? How?
During angiogenesis - by secreting hyaluronidase and plasminogen activator.