Chapter Extracellular Matrix

Question 1

What is the extracellular matrix?

Answer 1

1. 3D network of proteins and polysaccharides
2. Most abundant in connective tissue.
3. Supports sheets of epithelial cells and surrounds muscle cells, adipose cells, and peripheral nerves.

Question 2

What is the basement membrane?

Answer 2

Thin layer of ECM and fibrous proteins that anchors and supports epithelium.

• ties epithelium to connective tissue beneath it
• acts as protective barrier and filter

Question 3

Basal Lamina

Answer 3

1. Component of the basement membrane
2. Composed of ECM proteins secreted by epithelial cells
   3 example - Skin
   a. Outer epidermis layer-epithelial cells
   b. Middle dermis layer - connective tissue.
   c. Deeper subcutaneous layer

Question 4

What does ECM do?

Answer 4

1. Supports adhesion of cells
2. Transmits signals through adhesion receptors.
3. Binds, stores, and presents growth factors
4. Shapes tissue structures.
5. Guides and supports migrating cells

Question 5

Collagen type 1 (fibril forming)

Answer 5

• form connective tissue of skin, bone, tendon, ligaments, connective tissue layers of muscle and nerves, capsules that surround internal organs, and cornea

Question 6

Collagen Type 4 (network forming)

Answer 6

• Forms flexible sheet-like mesh due to breaks in triple helix
• important to molecular filtration, such as glomerulus which filters blood to form urine.

Question 7

Collagen type 7 (anchoring fibrils)

Answer 7

• keeps basement membrane intact

- crucial for functional integrity of epidermis-dermis junction in skin

Question 8

Osteogenesis imperfecta

Answer 8

• affects Type 1 collagen (fibril-forming)

- leads to weak bones that fracture easily

Question 9

Alport syndrome

Answer 9

• Affects Type 4 collagen (network-forming)

- Causes progressive nephritis, hearing loss, and ocular lesions

Question 10

Dystrophic epidermolysis bullosa (DEB)

Answer 10

1 epidermolysis bullosa is inherited diseases in which skin blisters in response to minor injury, hear or frictions from rubbing or scratching.
2- DEB affects type 7 collagen (anchoring fibril)
3- Important for anchoring epidermis to dermis

Question 11

What allows collagen 4 to be more flexible than collagen 1

Answer 11

Breaks in the triple helix structure

Question 12

Glycosaminoglycans

Answer 12

• long chain of disaccharides

- one sugar usually sulfated.

Question 13

Proteoglycans

Answer 13

• very heterogenous in size and composition
• regulate distribution of extracellular signaling molecules
• modulate signaling events at cell surface
• serve as structural constituents of ECM
• regulate movement of molecules between intracellular and extracellular compartments
• fibroblast growth factor has to bind to PG in order to activate its cell surface receptor.
• PG help form filtering apparatus in kidney by acting as molecular sieve in glomerulus
• aggregate major PG in cartilage, enzymatic destruction one of the early signs of arthritis
• enzymes that degrade PGs are important because they allow growth factors to be released when needed.

Question 14

Fibrillin

Answer 14

• fibrillin-1 and fibrillin-2
• forms microfibrils and associate with elastic fibers in ECM
• found in skin, lens of eye, aorta, periosteum.
• provides scaffold for tissues
• fibrillin-1 gene mutated in Marfan syndrome either has defective protein or lower amounts present in ECM

Question 15

Marfan syndrome

Answer 15

Malformations of digits, limbs, and anterior chest wall

• myopia due to lens dislocation
• aneurysm due to large lower aorta with weak walls

Question 16

Fibronectin

Answer 16

-two large subunits connected at their carboxyl termini by disulfide bonds
- multiple forms of protein present
- plasma forms are soluble and circulate in blood; non-adhesive
- cell/matrix forms are insoluble and found on surfaces of cells; involved in adhesion
- forms generated from one gene by alternative splicing.
Functions:
-blood clotting - plasma form attaches to fibrin in clot, which attracts fibroblasts to site.
-Wound healing, platelet adhesion and aggregation, cell adhesion, binding to bacteria, fetal fibronectin used to screen form premature delivery

Question 17

Lamin

Answer 17

• composed of 3 chains which form cross-shaped structure
• interacts with collagen 4 and PGs
• has tissue specific isoforms
• alpha3, beta3, and gamma2 chains form laminin 5 which is in skin
  a. Connects epidermis to dermis
  b. Defects in any chain can cause junctional epidermolysis bullosa (JEB)

Question 18

Which of the following ECM molecules is defective in Marfan syndrome

Answer 18

Fibrillin

Question 19

Matrix degradation

Answer 19

1. Regulated turnover of ECM is important in wound healing, bone remodeling, migration of white blood cells into tissues in response to injury and reproduction.
2. excessive/inappropriate ECM degradation can cause arthritis, multiple sclerosis, tooth decay, cardiovascular disease, chronic obstructive pulmonary disease and cancer metastasis

Question 20

Matrix metalloproteinases

Answer 20

1. ECM degradative enzymes

2. Require Zn or Ca to function

Question 21

Regulation of Matrix degradation

Answer 21

1. Proteases secreted as inactive precursors that can be activated locally
2. Action of proteases confined to specific areas by secreted protease inhibitors.
   - a tissue inhibitors of metalloproteinases

Question 22

Stages of Wound Repair

Answer 22

1. Inflammatory
2. Proliferation
3. Remodeling

Question 23

Role of ECM molecules and MMP’s in inflammatory stage

Answer 23

• fibronectin part of blood clot

- MMPs facilitate release of cells that migrate into wound

Question 24

Role of ECM molecules and MMP’s in proliferative stage

Answer 24

1. cells migrate to cover wound and form new epidermis
2. provisional matrix formed
3. connective tissue cells (fibroblasts) synthesize collagen, predominantly type 3
4. Fibroblasts synthesize matrix form of fibronectin, which during healing is replaced by collagen
5. GAGs such as hyaluronan allow cells to migrate
6. PGs store and the release growth factors
7. MMP expression up-regulated to degrade ECM proteins

Question 25

Role of ECM molecules and MMPS in the remodeling stage

Answer 25

1. Normal constituents of skin synthesized 2. protein complexes become more organized. 3. Previously synthesized collagen, fibronectin, and hyaluronan degraded 4. Collagen 3 replaced by collagen 1

Question 26

What happens if there is too much MMP production?

Answer 26

Wounds don't heal | - occurs in chronic wounds, MMP activity is prolonged

Question 27

A patient presents with a congenital defect in bone formation. Which of the following ECM proteins is most likely to be the cause?

Answer 27

Collagen.

Question 28

Which of the following ECM proteins is defective in dystrophic epidermolysis bullosa?

Answer 28

Collagen

Question 29

A 6-month old boy presents with junction all epidermolysis bullosa. Which of the following proteins is defective in this patient?

Answer 29

Laminin 5