Extracellular Matrix

Question 1

Extracellular Matrix

Answer 1

• Groups of cells organize the environment around them and secrete extracellular matrix (ECM)
• ECM is collection of fibers that support and connect the cells and integrate tissues
• Different tissues have significantly different ECM, but ECM is made up of generally 3 components
  
  1. Protein fibers
  2. complex carbohydrates
  3. Cell-matrix adhesions

Question 2

Collagen

Answer 2

• A family of fibrous proteins that give strength and rigidity to the extracellular matrix
• Fibrous, helical protein
• Fibers can be oriented in parallel or obliquely to create strength in different dimensions
• Multiple different collagens with differential expression
• Gives strength, rigidity to extracellular matrix
• ECM strength and rigidity inluenced by:
  
  • Type of Collagen, Amount of Collagen
  • Crosslinking of Collagen, Orientation of Collagen

Question 3

Elastin

Answer 3

• A family of fibrous proteins that give flexibility and elasticity to the extracellula matrix
• Fibrous, relatively disordered protein
• Relaxed state is highly coiled, tension causes the fibers to straighten, returning to relaxed state recoils the fiber
• Highly crosslinked, which confers memory on the matrix
• Gives flexibility, stretch-ability (elasticity) to the ECM
• Very important in lung, large arteries, skin, intestines, etc.

Question 4

Glycosaminoglycans and Proteoglycans

Answer 4

• Long carbohydrate polymers, often highly charged, that absorb water and make up most the volume of ECM
• Glycosaminoglycans (GAGs) are long polymers of repeating sugar units and are usually significantly negatively charged
• Proteoglycans are fibrous proteins with GAGs attached
• A large portion of the volume of extracellular matrix is filled with GAGs and Proteogycans
  
  • Most of the extracellular matrix’s mass is the protein content
• Most GAGs arefound as proteoglycans (except Hyaluronan)
• GAGs are very hydrated and act almost as ‘sponges’ to hold tissue fluid
• The concentration and make up of GAGs/proteoglycans in a tisue can significantly affect the movement of water and solutes in a tissue
• GAGs also are highly charged and repulse each other, giving volume (and resistance to compression) to the ECM

Question 5

Glycosaminoglycans and Signaling

Question 6

Clinical Correlation - GAGs and Cartilage

Answer 6

• GAGs are found ubiquitously in the body, but are especially important in cartilge
• A high concentration of highly charged GAGs turns cartilage into a ‘stiff water balloon’ that cushions the joint
  
  • Chondroitin Sulfate
• Other GAGs act as ‘oil’ absobing water and turning into a viscous liquid that lubricates the joint
  
  • Hyaluronic acid

Question 7

Adaptor Proteins

Answer 7

• 2 classes of proteins that crosslink the main components of ECM and bind to membrane proteins
• 2 protein families link the ECM to the cell
• Laminins:
  
  • Made up of 3 strands with a triple helix structure
  • Binds to Collagen IV, some GAGs, and to cell surface receptors
  • Crosslinks the matrix and connects to the cell
  • Especially present in the basal lamina (thus laminins)
• Fibronectins:
  
  • Made up to 2 strands
  • Binds to collagen, some GAGs, some proteoglycans, and to cell surface receptors
  • Crosslinks the matrix and connects to the cell

Question 8

Membrane Proteins - Integrins

Answer 8

• Integrins are transmembrane proteins that bind to ECM adapter proteins
• Integrins are transmembrane proteins that bind to fibronectins or laminins to attach the cell to the ECM
• Integrins can also attach to the cytockeleton through adapter proteins (usually MF, but IF in hemidesmosomes)
• Integrins facilitate communicatin and cohesion between the intracellular matrix (cytoskeleton) and the extracellular matrix

Question 9

ECM - Cell Juntions

Answer 9

• Focal Adhesions:
  
  • Made up of integrins bound to actin filaments
  • Similar to adherens junctions with integrins attaching to matrix instead of cadherins attaching to other cells
  • Found primarily in non-epithelial cells, especially migrating cells
  • Can be very dynamic adhesions
• Hemidesmosomes:
  
  • Made up of integrins bound to intermediate filaments
  • Similar to desmosomes with integrins attaching to matrix instead of cadherins attaching to other cells
  • Found primarily in epithelial cells
  • Often very stable adhesions

Question 10

ECM Remodeling

Answer 10

• ECM is not static but can be remodeled in a variety o different situations. A significant contributor to matrix remodeling are the matrix metalloproteinases
• Like everything in thebod, the ECM is not static
• Cell can remodel the ECM by difesting the current ECM and secreting new ECM
• One of the main factors in ECM degradatino and remodeling are the matrix metalloprteases (MMPs)
• Different MMPs can digest specific ECM components (especially collagens) when activted by the cell
• MMPs are expressed during wound healing, migration (especially immune cells), etc.

Question 11

Clinical Correlation - ECM Dysregulation and Metastasis

Answer 11

• For tumor cells to migrate away from teh primary tumor, the ECM has to be significantly remodeled
• Basal lamina is a dense meshwork of fibers that are not easy to push through, it needs to be changed into straight paths of collagen fibers that the cell can migrate down
• Matrix metalloproteases (MMPs) are often dysregulated in cancer which facilitate matrix reorganizaiton and metastasis

Question 12

Clinical Correlation - MMPs and Oral Melanoma

Answer 12

• Several MMPs may be overexpressed and mis-regulated in canine oral melanomas
• One study gound that MMP2 mRNA had an almost 90x increase over normal controls in early stage OM and almost 30x in late stage OM
• MMP14 also had a 5x (early) or 3x (late) increase over normal controls
• The mis-regulation of extracellular matrix remodeling likely contributes to the extreme metastatic potential of OM
• Anti-MMP treatment has been investigated as an anti-tumor/anti-metastatic, unfortunately none have worked