Extracellular Matrix Flashcards
Functions of ECM
- cellular division
- motility
- differentiation
- adhesion
- structure
Components of ECM
- Structural Proteins = collagens and elastins (strength and flexibility)
- Proteoglycans =protein-polysaccharides complexes (matrix for collagen and elastins to be embedded in)
- Adhesive Glycoproteins = Fibronectins and Laminins (attach cells to matrix)
Collagens
- Structural Proteins
- Most Abundant Protein in vertebrates (25% - 30% of total body protein)
- Abundant in tendons and ligaments
- Secreted by several connective tissue cells (ex-fibroblasts)
- Rigid Triple Helix structure with polypeptide chains high in glysine, hydroxylysine, and hydroxyproline
- Have incredible strength
Collagen Cross Linking
When Produced: Collagen bundles cross-linked which strengthens collagen bundle and helps withstand high stress
With Aging:
Abnormal Crosslinking which leads to loss of joint function
hypermobility
deficiency in collagen synthesis or assembly (collagenase)
Elastin provides….
- flexibility
- elasticity
What is elastin?
- proteins rich in glycine and proline
- molecules of elastin are crosslinked BETWEEN lysines
Why is elastin flexible?
- can form variety of confirmations
- the tension in it allows for stretching
- no tension when relaxed so no stretching
Why does skin become wrinkled and joints become inflexible as we age?
Elastins are lost as we age
What is supravalvular aortic stenosis (SVAS)?
- inherited obstructive vascular diesease that affects the aorta, carotid, coronary and pulmonary arteries
- Mutation in elastin gene disrupts elastin protein synthesis and result in narrowing of aorta or pulmonary vessels
- This can lead to a heart murmur and ventricular hypertrophy
- Not frequently seen
- defect is located just above the aortic valve
- Affects some large dog breeds = Newfoundland, Golden Retriever, Boxer, and Rottweiler
Proteoglycans
- Make up Gel-like network that surrounds collagen and elastin
- Proteoglycans are glycoproteins
What are glycoproteins?
- Protein with glycoaminogylcans
- Up to 95% carbohydrate
Functions of Proteoglycans
- Receptors
- Filtration
- Shock Absorption
- Trap water = >50% Times Their Weight
Hyaluronate
- Proteoglycan that acts as the backbone in cartilage
- also acts a free molecule
Function
- lubricates any place with friction = joints
- found on suface of migrating cells
- disappears upon cell-to-cell contact- facilitate cell migration by making matrix more water-soluble
T/F: Hyaluronan is quite large in comparison to other ECM components
True.
Hyaluronan is much larger than other ECM components.
Glycosaminoglycan Side Chains can be used for classification. What are the 3 types and their uses?
- Chondroitin Sulfate = cartilage/ osteoarthritis
- Keratan Sulfate = cornea, cartilage, bone, cushion
- Heparin/ Heparin Sulfate = Anticoagulant, bind growth factors, important role in inflammation, entry of virus into cells (herpes, rabies)
Heparin/ Heparan Sulfate
- Heparan Sulfate is found in every cell of body and has side chains made of D-glucosamine/ L-iduronic acid
- Heparin is one member of the Heparan Sulfate Family and serves as an anticoagulant
- Other Family Members bind growth factors, play an important role in inflammation, and entry of viruses into cell like herpes and rabies
Fibronectin
- widely distributed
- most common adhesive glycoprotein
- can be soluble, insoluble, or partialy soluble (can be from same gene due to alternative splicing)
Roles of Fibronectin
- maintains cell shape
- possible role in cancer
- blood clotting
- wound healing
- cell movement
Fibronectins Role in Cancer
- Many carcinomas are unable to synthesize fibronectins, lose normal shape, and cells detach from ECM
- Give fibronectin and cells revert to normal shape, bind to ECM, and are no longer malignant
How does fibronectin connect into blood clotting?
-recognizes fibrin (blood clotting protein) that is attached to blood platelets
What does fibronectin do in wound healing?
guides immune cells to wound
Where are laminins mainly located?
Basal Laminae
Basal Laminae
- Thin sheet of EC material (approx. 50nm thick)
- underlies epithelial cells
- separates ECM from epi cells
- Surrounds muscle cells, fat cells, and Schwann cells
Properties of Basal Lamina
- Structural Support
- Permeability Barrier = kidney -> can let in small proteins, but not blood into urine
- Cell Migration
T/F: When ECM has been damaged and is remodeled, it is laid down in the same pattern as it was originally.
False.
ECM is initially very well organized and structured. After damage and remodeling, it is not well organized and structured.
Why is ECM constantly being remodeled?
- growth
- changes in mechanical forces
- heal
Synthesis Of ECM
- Under Transcriptional (genesis) Control by parent cell types
- osteoblasts
- chondrocytes
- fibrocytes
- Cells respond to:
- paracrine signaling by growth factors
- physical (lack of) contact with other cells and ECM
Degrading ECM
-Accomplished by enzymes = metalloproteinases and serine proteases
What does metalloproteinases need for ECM?
- require Zinc or Calcium
- usually specific for 1 ECM Component
How do serine proteases play into degrading ECM?
- cleave protein sequences at serine residues
- work with metalloproteinases
How can ECM degradation be stopped?
- Tissue Inhibitors of Metalloproteinases (TIMP1, 2 ,3, and 4) that form high affinity complexes with metalloproteinases that are irreversible
- Serine Protease Inhibitors that inactivate serine proteases
Alpha 1-antitrypsin deficiency
- Alpha 1-antitrypsin is produced in liver and macrophages = protects lungs from neutrophil elastase enzyme, which can disrupt connective tissue
- Deficiency caused by defective production of alpha 1-antitrypsin
- Emphysema/COPD and liver disease (cirrhosis) can result
- Treatment is IV infusions of alpha 1-antitrypsin
Panniculitis
- alpha 1-antitrypsin deficiency in dogs leading to rare skin condition
- characterized by hardened skin with painful lumps or patches
- can vary in severity
- can occur at any age
