Extra Cellular Matrix

Question 1

Extracellular Matrix

Answer 1

The structural Framework in which cells organize, move and interact

Provides sites for cell adhesion and a conduit for exchange of cell nutrients and wastes

Question 2

Promerties of the ECM

Answer 2

• It dictates tissue architecture and organization
  
  • has specific features for each tissue/organ
    
    • bone, liver, brain, lung, intestine, skin
• It regulates or modifies many cell activities
• I serves as a reservoir of growth factors and bioactive molecules
• It is constantly remodeling and changing.

Question 3

Processes influenced by ECM

Answer 3

• The ECM plays a major role in:
  
  • Embryogenesis
  • Fibrosis
  • Would healing
  • Cell behavior
    
    • morphogenesis, differentiation, adhesion, migration, apoptosis
  • Carcinogenesis
    
    • Tumor invasion and metastasis

Question 4

Componenets of the ECM

Answer 4

• The “matrisome” consists of over 300 different proteins
• These components fall into 3 categories:
  
  • Structural
  • Absorptive
  • Adhesive

Question 5

ECM:

Structural

Answer 5

• Structural components of the ECM build the framework for cells to exist upon and within
• Structural components include:
  
  • Collagen
    
    • many different types exist for different situations
  • Elastin
    
    • Most prominent where elasticity is needed

Question 6

Collagen Types

Answer 6

There are at least 28 different types of collagen

1. structural collagen of most tissues
2. Major component of cartilage
3. Basement membranes

Question 7

Collagen Disorders:

Marfan Syndrome

Answer 7

• A mutation in the gene encoding fibrillin-1
  
  • Fibrillin-1 is a structural component of microfibrils and regulates formation of elastic fibers
  • Elevated levels of TGF-beta also occur and contribute to the disease
• Features include, tall, slender build, disproportionally long fingers and toes, lens dislocation, and aortic weakening

Question 8

Dermatosporaxis

Answer 8

Ehler-Danlos Syndrome

• A group of inherited connective tissye disorders characterized by defective collagen synthesis
• Dermatosporaxis is one varient of this condition

Question 9

ECM:

Absorptive

Answer 9

• These absorb water and other soluble substances which bath surrounding cells
• Major absorptive components:
  
  • Glycosaminoglycans (GAGs)
    
    • these are polysaccharides consisting of 4 main groups:
      
      • hyaluronic Acid
      • Heparan sulfate
      • Chondroitin/dermatan sulfate
      • Keratan sulfate
    • Proteoglycans
      
      • these are proteins with GAG side-chains
• These exert important osmotic pressures to help maintain water balance

Question 10

Proteoglycans and Edema

Answer 10

• Edema is the excessive accumulation of fluid in the extracellular matrix or within body cavities
• Edema has various causes, one of which is a change in concentrations or properties of absorptive molecules in the ECM

Question 11

ECM:

Adhesive

Answer 11

• Sites of attachment for structural ECM components and cells
• Adhesive components:
  
  • Fibronectin
  • Laminin
  • Many others
• These mediate interactions of fixed or mobile cells with the ECM

Question 12

Fibronectin and Wound Healing

Answer 12

• A glycoprotein that attaches to integrins as well as extracellular matrix proteins such as collagen, fibrin, and proteoglycans
• Fibronectin is critical for wound healing
  
  • provieds binding sites for macrophages, endothelium, and fibroblasts during tissue repair and healing
  • Contributes to formation of the granulation tissue matrus
  • Can influence cell function and protein expression

Question 13

Fibronectin

Answer 13

• Other roles of fibronectin include:
  
  • Cell migration and differentiation during embryogenesis
    
    • fibronectin deficiency can lead to embryonic death, or defects in neural and vascular development
  • Hemostasis
    
    • in conjunction with fibrin
  • Carcinogenesis
    
    • May promote tumor growth and survival

Question 14

Injury to the ECM

Answer 14

• General patterns of injury
  
  • increased destruction
  • decreased production
  • Excessive production
  • Depostition of abnormal substances

Question 15

Increased Destruction of ECM

Answer 15

• The ECM exists in a dynamic balance of production and degredation
  
  • fibroblasts produce collagen
  • Matrix metalloproteinases among other enzymes degreade collagen
    
    • MMP 1 = collagenase
• Decreased ECM occurs when the balance of degredation exceeds production
• Causes include:
  
  • Excessive MMP activity:
    
    • this has been associated with various conditions, including vascular disease, neoplasia, skin and muschuloskeletal disorders
  • Inflammation:
    
    • Lysosomal enzymes are released into the ECM
      
      • Excessive amounts of MMP
        
        • collagenases and elastases
    • Oxygen free radivals and cytokines damage ECM
  • Immunologic reactions
    
    • immunologic activation of inflammatory responses
• Morphology:
  
  • Gross:
    
    • Corresponds to the different types of necrosis
  • Histologic:
    
    • Collagen is swollen, uniformly eosinophilic fragmented, or absent
    • Inflammation is usually present

Question 16

Decreased Production of ECM

Answer 16

• Causes:
  
  • occur as inherited diseases of collagen formation
    
    • collagen dysplasia
  • Nutritional deficiencies can influence ECM production
    
    • Vitamin C is a critical element for collagen formation and maintenance
• Morphology:
  
  • Gross:
    
    • Skin is very distensible and fragile
    • Tears in the skin
  • Histologic:
    
    • No abnormalities in come cases
    • Collagen of vairable size and shape
    • Abnormal collagen organization

Question 17

Excessive Production of ECM

Answer 17

• This is predominately associated with healing in irreversibly damaged tissue
  
  • fibrosis and scar formation
• Excessive fibrosis can interfere with tissue and organ function
  
  • Fibrosis can have major detrimental effects when located in critical tissues
    
    • heart, liver, kidneys, etc.
• Causes:
  
  • Upregulation of collagen-producing cells
    
    • predominately firbroblasts
    • Shift in ECM homeostatsis or metabolic problem
  • Any stimulus resulting in irreversibly damaged tissue
    
    • Tissue is replaced by collagen as part of healing
      
      • fibrosis and scar formation
• Morphology:
  
  • Gross:
    
    • Dense, white fibrous tissue replacing normal tissue
    • abnormal relationships between tissues and organs
      
      • excessive fibrosis can interfere with organ function
  • Histologic:
    
    • Densely packed collagen
    • Initially increased fibroblasts
    • Later mainly collage with a few firbroblasts

Question 18

Depostition of Substances in ECM

Answer 18

• Abnormal substances can be deposited in both normal and abnormal ECM
• Common substances depostied:
  
  • Amyloid
  • Calcium
  • Iron
  • Excessive collagen

Question 19

ECM depostition:

Amyloid

Answer 19

• Chymically diverse protein that has a B-pleated sheet confirmation
  
  • Composition
    
    • 95% fibrillar proteins
    • 5% other proteins
      
      • serum amyloid P protein
      • Proteoglycans
      • Glycosaminoglycans
• Over 30 biochemically distinct forms of disease-associated amyloid have been described
  
  • Most common forms:
    
    • Amyloid light chain (AL) protein
      
      • immunoglobulin light chains
    • Amyloid-associated (AA) protein
      
      • derived from serum AA produced by the liver
    • AB amyloid
      
      • fragment derived form amyloid precursor protein (APP)
• Cause:
  
  • Due to abnormal folding of amyloid proteins
    
    • deposition is usually due to :
      
      • Normal protein that have a tendency to misfold when produced in excess
      • Abnormal proteins formed due to mutations
    • Misfolded amyloid can’t be degraded and accumulates extracellularly in the ECM
      
      • May be a defect in normal degradative processes
      • May be an abnormal protein that can’t be degraded
• Morphology:
  
  • Gross:
    
    • Deposition can occur either locally or systemically
    • Affected organs are enlarged, firm, and discolored
    • Detectable with lugol’s iodine and sulfuric acid
  • Histologic:
    
    • Eosinophilic, acellular, amorphous, fibrillar extracellular protein that displaces normal tissue components
      
      • some types of amyloid can be intracellular as well
    • Stains with congo red dye
      
      • produces apple-green fluorescence with polarized light

Question 20

ECM Deposition:

Amyloid:

Syndromes

Answer 20

• Characterized by amyloid deposition have been described, including:
  
  • Primary amyloidosis
  • Secondary (Reactive) amyloidosis
  • Amyloidosis of aging
  • Endocrine amyloidosis
  • Familial Amyloidosis

Question 21

ECM deposition:

Amyloid:

Primary amyloidosis

Answer 21

• This is usually associated with immunological dyshomeostasis and deposition of AL protein
• It is most commonly associated with plasma cell neoplasia
  
  • neoplastic cells produce excessive amounts of immunoglobulin and immunoglobulin light chains

Question 22

ECM Deposition:

Amyloid:

Secondary Amyloidosis

Answer 22

• Usually associated with chronic inflammation and tissue destruction with deposition of AA protein
• Cytokines and cell damage associated with chronic inflammation increases production of SAA
• Abnormal breakdown of SAA or sturctural abnormalities in the SAA results in deposition in the ECM
• Most common form in domestic animals

Question 23

ECM Deposition:

Amyloid:

Amyloidosis of aging

Answer 23

• Deposition of AB amyloid can occur in the brain of old dogs
  
  • this type is characteristic of Alzheimer’s disease of humans
• Deposition less often occurs in heart, GI tract, and lungs of old dogs

Question 24

ECM Deposition:

Amyloid:

Endocrine Amyloidosis

Answer 24

• Amyloid is deposited in the pancrease (islets) of cat
  
  • protein is derived from a normal product of pancreatic islet B cells
• Amyloid deposition can result in Type 1 diabetes mellitus
• Also occurs in some non-human primates and humans

Question 25

ECM Deposition:

Amyloid

Familial Amyloidosis

Answer 25

• Systemic Deposition of AA amyloid occurs specifically in some breeds of dogs and cats
  
  • abyssinian and siamese cats
  • Shar-Pei dogs
• Hereditary
  
  • SAA may be abnormal
  • There may be some chronic inflammatory component in some cases
• Kidney and liver are most commonly affected

Question 26

ECM Deposition:

Calcium

Answer 26

• Calcification (mineralization) can occur in either normal or abnormal ECM
• Causes:
  
  • Mineralization can occur due to two basic processes
    
    • Dystrophic mineralization
    • Metastatic mineralization

Question 27

ECM Deposition:

Calcium:

Dystrophic Calcification

Answer 27

• Process occus in necrotic tissue
• Calcium binds to damaged membrane phospholipids and initiates calcium cyrstal formation
  
  • cell can no longer prevent calcium influx into the cytosol
• This is a reflection of local tissue damage, and not a systemic distrubance in calcium homeostatis
• Common Locations:
  
  • Heart
  • Skeletal Muscle
  • Inflammatory Lesions
    
    • granulomas
  • Skin
    
    • calcinosis cutis associated with hyperadrenocorticism

Question 28

ECM Deposition:

Calcium

Metastatic Clacification

Answer 28

• This occurs in normal, viable tissue
• Reflection of calcium dyshomeostatis
  
  • secondary to hypercalcemia
• Calcification is initiated by local alkalinity and elterations in collagen structure
• Common situations include:
  
  • Renal failure
  • Vitamin D toxicity
  • Pseudohyperparathryroidism
    
    • paraneoplastic condition associated with PTH-like protein
  • Clalcification if often systemic

Question 29

ECM Deposition:

Calcium

Morphology

Answer 29

• Gross:
  
  • Gritty and white deposits in tissue
• Histologic:
  
  • Purple material that either incorporates into normal sturctures or disrupts the noraml morphology of the tissue

Question 30

ECM-associated Disease:

Epidermolysis bullosa

Answer 30

• A group of conditions characterized by skin fragility and blistering
  
  • causes include abnormal collagen Typer VII, keratin, laminin, and integrins
    *

Question 31

ECM-associated Disease:

Collagen Defects

Answer 31

• Osteogenesis imperfecta
  
  • abnormal Type 1 collagen
• Ehlers-Danlos Syndrome
  
  • Defects in collagen or metalloproteinases

Question 32

ECM-associated Disease:

Muscular Dystrophies

Answer 32

Defects in laminin or Type VI collagen, and decreased dystrophin levels

Question 33

ECM-associated Disease

Osteoarthritis and Intervertebral disk Disease

Answer 33

Degeneration of multiple matrix components

Question 34

ECM-associated Disease:

Vascular Disease

Answer 34

Atherosclerosis and aneurysm

Question 35

ECM-associated Disease:

Neoplasia

Answer 35

Invasion, angiogenesis, metastasis

Question 36

ECM-associated Disease

Diabetes mellitus

Answer 36

Excessive collagen gylcation and cross-linking and stiffening

Question 37

ECM-associated Disease:

Chondrodysplasia

Answer 37

Abnormal type 2 collagen