Why is the extracellular matrix important in medicine?
-It provides the mechanical characteristics of tissue -Abnormalities in the metabolism of extracellular matrix molecules lead to various connective tissue diseases.
What is the extracellular matrix?
The "ground substance" in connective tissues between cells.
What are the 5 main components of the extracellular matrix?
1)Collagens - provide the tensile strength of tissues 2)Elastic fibers- provides resilience of the tissue 3)Proteoglycans- provides resilence 4)Hyaluronan- provides resilience 5)Glycoproteins- mediate adhesive interactions between other matrix molecules or between cells and matrix molecules
In general what are Collagens?
-The main fibrillar protein in CT -Has a characteristic triple helical structure -The triple helical structures are then heavily cross-linked to provide extra stability
What are the 3 main groups of Collagens?
1) Fibril forming 2) Network forming 3)Fibril-associated (associate with Type I,II, and III
Fibril forming collagens includes what Types
-includes Type I, II, and III
Collagen Type I, tissue distribution
-skin, bone, tendon, blood vessels, and the cornea
Collagen Type II, tissue distribution
-Cartilage, intervertebral discs, vitreous body
Collage Type III, tissue distribution
-blood vessels and fetal skin
Network-forming collagens includes what Types?
Type IV, and Type VII
Collagen Type IV tissue distribution
Collagen Type VII tissue distribution
beneath stratifies squamous epithelia
Fibril-associated collagens include what Types
Type IX and Type XII
Collagen Type IX tissue distribution
Collagen Type XII tissue distribution
tendon, ligaments, and some other tissues
What is Procollagen?
-Procollagen is a precursor to the collagen chain that has propeptides located on the N and C-terminus, -these propeptides will later be proteolytically cleaved after 3 procollagen chains assemble into a triple helix
Collagens are composed of what?
-3 alpha chains (can be identical or different)
-The helical chains are composed of Gly-X-Y repeats -X is usually proline -Y is usually hydroxyproline
Where does synthesis of the procollagen chain occur?
occurs in the RER
Synthesis of the alpha procollagen chains
-Genes for the procollagen chains are transcribed into mRNA -the mRNA is translated on the RER into prepro-alpha-polypeptide chains that are extruded into the lumen of the RER. -the signal sequence is removed in the lumen of the RER -Certain proline and lysine residues are hydroxylated -Some of the resulting hydroxylysines are then glycosylated
Where does the assembly of the procollagen triple helix occur?
in the RER
Assembly of the procollagen triple helix
-3 procollagen alpha chain assemble from the C to the N-terminal end -Intrachain and interchain disulfide bonds form at the C-terminal propeptide extension -The triple helix is then formed (through a zipper like folding) and is held together by H-bonds
What helps stabilize the formation of the procollagen triple helix?
Where does cleavage of the procollagen propeptide extensions occur?
In the extracellular matrix
Proteolytic cleavage of the propeptide extensions
-The procollagen molecule is secreted from a Golgi vacuole into the extracellular matrix -The N and C-terminal propeptides are then cleaved off by procollagen peptidases producing a tropocollagen monomer -These monomers then assemble into fibrils
-are formed from collagen monomers that associate in a staggered mannor -They are stabilized by covalent cross-links between the collagen monomers
How is the triple helix of collagen stabilized?
-Through H-bonds and hydroxyproline
What enzyme produces Hydroxyproline?
prolyl hydroxylase through hydroxylation of a proline residue
What is prolyl hydroxylase and what cofactors does it require?
-Prolyl hydrolase produces hydroxyproline
-Requires Fe2+ and Vit C (ascorbate) as cofactors
What residue participates in the crosslinking of collagen chains?
What enzyme produced Hydroxylysine?
What cofactors does lysyl hydroxylase require?
Fe2+ and Vit-C (ascorbate)
How are the covalent crosslinks within collagen fibers created?
-Through the formation of oxidized lysine and hydroxylysine residues
What oxidizes lysine and hydroxylysine?
What cofactors does Lysyl oxidase require?
Where does the oxidation of lysine and hydroxylysine during the formation of covalent crosslinks within collagen fibers take place
In the extracellular matrix
What is the main collagen in the basement membrane?
Type IV collagen
Assembly of the Type IV collagen network
-occurs in the extracellular space -2 Type IV molecules attach at their C-terminal end forming a dimer -Dimers then associate through their N-terminal ends forming tetramers and eventually large networks
Vit-C deficiency (Scurvy)
-Arises from a lack of fruits and vegetables in the diet -Prolyl and lysyl hydroxylases do not function (from the lack of their Vit-C cofactor) -Resulting in a collagen triple helix that is less stable with reduced crosslinking
-Results from a mutation in Type V collagen (fibril-associated) -Causes: hyperextensive skin, delayed wound healing, atrophic scars, and joint hypermobility
Ehlers-Danlos -vascular type
-Results from a mutation in Type III collagen -causes: arterial, intestinal, and uterine ruptures
Ehlers-Danlos - Kyphoscoliotic type
-results from a mutation in Lysyl hydroxylase -causes: hyperextensive skin, delayed wound healing, easy bruising, thin scars, joint hypermobility, progressive kyphotic scoliosis
-Types I, II, III, and IV are associated with Type I collagen mutation -symptoms very among the 7 different types
Characteristic symptoms of Osteogenesis imperfecta
-increased incidence of fractures -short stature -grey of brown teeth that wear down easily (dentinogenesis imperfecta) -blue sclera
-Caused by a mutation in Type IV collagen -Mainly effects the glomerular basement membrane and can lead to renal failure
Main symptoms of Alport Syndrome
-hematuria -proteinuria -renal insufficiency
What is Elastin
-The major component of elastic fibers -Allows tissues to stretch and contract
Where are elastic fibers main localization?
in blood vessels and the lungs
Where is Elastin synthesized?
-In the ER, and is then secreted as monomers. -In the extracellular space, lysine residues are oxidized by lylsyl oxidase, and then crosslinks form between elastin monomer
What is required for the correct assembly of elastic fibers?
requires microfibrils formed by fibrillins
-a1-antitrypsin is a natural inhibitor of neutrophil elastase and is responsible for preventing excessive degradation of elastin.
-In this deficiency there is not enough a1-antitrypsin to inhibit neutrophil elastase, leading to excessive degradation of elastin -in a1-antitrypsin deficiency, the lung has lower elastin content, which can lead collapse of the small airways when the patient exhales and leads to emphysema (manifests as SOB)
what is Neutrophil elastase
an enzyme responsible for degrading elastin
What social activity exacerbates the conditions in a1-antytrypsin deficiency?
-caused by a mutation in Fibrillin-1 -Microfibrils are deficient, which means that elastic fibers will also be deficient (since microfibrils are essential for elastic fiber assembly)
Main symptoms of Marfan syndrome
-Skeletal: very tall, kyphosis, disproportionally long limbs and digits, hyperflexible joints. -Ocular: dislocation of the lens of the eyes (extopia lentis) -Cardiovascular: Dilation of the aorta, heart valve problems
In CT, why is there a dynamic interaction between cells and the Ex. matrix?
-In order to maintain the function of the tissues
- Resident cells <----> extracellular matrix resident cells synthesize the matrix, while the matrix provides an optimal environment for the cells
How do resident cells bind to the extracellular matrix?
-Through cell surface receptors -These receptors allow the cells to sense changes in the extracellular matrix and respond
What is an example of a resident cells response to a change in the extracellular matrix, such as tissue damage
-To restore the integrity of the tissue by re-synthesizing the extracellular matrix.
What are the main receptors that anchor cells to the extracellular matrix?
Integrins (aB dimer)
Integrins can bind to what?
-Collagens and glycoproteins, such as fibronectin or laminin
Integrin-laminin interactions are essential for what?
-For the correct formation of basement membranes
What are laminins
-Basement membrane proteins -Heterotrimers (built from a, B, gamma chains) that are stabilized by disulfide bonds
where does the synthesis of laminin chains occur?
-In the ER while the chain assembly occurs in the golgi
Where does the laminin chain assembly occur?
-laminin chain synthesis occurs in the ER -Laminin chain assembly occurs in the Golgi
How do laminins interact with the basement membrane prteins and integrins?
- through cell surface interactions
Junctional epidermolysis bullosa
-Cause by mutations in certain Laminin and Integrins (leading to a deficiency) -Mainly affects the basement membranes below the epidermis and mucosal membranes
What are the main symptoms of junctional epidermolysis bullosa??
-fragile skin that shows extreme blistering
Tissue remodeling of the extracellular matrix takes place during:
-Tissue differentiation (matrix composition changes) -Cell migration (cells have to "cut" through the matrix
What is needed in order to remodel the matrix?
-Cells in the extracellular matrix secrete Matrix metalloproteinases (MMP's)
What are Metalloproteinases?
-It degrades the current matrix proteins
What controls the action of Metallproteinases?
-Controlled by Tissue Inhibitors of MetalloProteinases (TIMPs) which are also secreted by the cells of the extracellular matrix
the extent of tissue remodeling is dependent on what?
-The ratio of MMPs to TIMPs
How to agressive tumors use MMPs?
-They secrete excessive amounts of matrix metalloproteinases (MMPs) in order to invade the surrounding tissues.