4.14.2010 Lecture 2 - ECM1. Tissue Types

a. There are four tissue typesi. Muscle Tissue

1. Smooth Muscle2. Cardiac Muscle3. Striated Muscle

ii. Nervous System Tissue1. Neuronal cells2. Non-neuronal cells

iii. Connective Tissue1. Bone

a. Osteocytesi. Mature bone cells

ii. Precursor is the osteoblast1. Secretes ECM during development of that

tissue2. Cartilage

a. Condroblastsi. Secrete ECM

3. Loose connective Tissuea. Fibroblasts

i. Secrete ECM4. Blood5. Lymphoid Tissue6. Made by cells

a. Undifferentiated form of the mature cells that are characteristic of that tissue type

iv. Epithelial Tissue1. Epithelia2. Epithelial Cells

a. Skinb. Intestinal Lining

3. Held to one another and to the basal laminaa. Held to one another by tight junctions and adherins

junctionsi. Linked to basal lamina by integrins

1. Integrins interact directly with the ECMii. Needs of basal lamina

1. Loose connective tissuea. This is where we see the most gel-like

structure in this type of connective tissue

b. Fibroblasst secrete LCTi. Collagen

ii. Elastin

iii. Proteoglycans (more gel-like)iv. Glycoproteins (more gel-like)

4. Use intermediate filaments that are connected to the junctions between the cells and with the cell interaction between the basal lamina to withstand stress

2. Connective Tissue Macromoleculesa. ECM is made of two types of macromolecules

i. Proteoglycans1. Protein core, which can vary, surrounded by GAGs

a. Glycosomino Glycansi. They are negatively charged repeating units of

sugars, polysaccharides, that covalently link themselves to the protein core, and useful in forming ECM because – charge attracts H20, creating a buffering sort of tissue that can withstand tensile stress and create a hydrated environment so cells can move and nutrients and waste can diffuse through and the cells can function because of those mobile molecules. Also cell motility

ii. Can link in complex waysiii. The more GAGs, the more water and the more

flexible that connective tissue isii. Fibrillar

1. Typesa. Collagenb. Fibronectinc. Elastin

2. Importancea. Strong Structuresb. Strength to the ECMc. Organization to the ECMd. Cell-ECM interaction

3. From organized structure of ECM, allowing ECM to withstand pressure

4. Holds tissue together when there is change or mechanical stress on the tissue

3. Collagena. Rheumatoid arthritis

i. Inflammatory response, autoimmune, that is though to be geneticii. Immune system attacks collagen in ECM

1. Unknown2. Causes pain and disfiguring of the joints

b. Made of alpha chainsi. Can assemble in a variety of ways

1. Results in the types of collagen madec. Types of Collagen

i. Type I – Fibrillar type1. 90% of ECM of the body

ii. Types can be differentiated by the roman numerals. Types can be placed into functional group:

1. Fibrillar Forming collagen2. Fibril Associated collagen3. Network forming collagen4. Transmembrane collagen

d. Synthesis of Collagen - ERi. Formed by the synthesis of an alpha chain

1. Amino acid structure varies2. All have high concentrations of proline and glycine amino acids

a. Proline: becomes heavily hydroxylated as the chain formsi. Form H bonds with neighboring amino acids

1. Helps hold alpha chains togetherb. Glycine

i. Smallest amino acid1. Present every third amino acid so the chains

can interact very closely and tightly3. Three alpha chains fold together to make a procollagen triple helix,

still in the ERa. On either end of the procollagen, amino acids hang off of

amino and COOH terminii. Eventually clipped, which allows continual assembly

1. Cannot occur until procollagen is secreted into cytoplasm

a. Procollagen peptidase cleaves of terminal amino acids to make a mature collagen molecule ready to form into the fibril and fiber forms

2. Assemblya. Procollagen align with one another

with overlapping regionsi. Creates striated pattern in the

fibrillar collagen and allows for strength of collagen fiber in mature state

ii. Collagen fiber is generated as fibril wind around one another (~270 of collagen molecules that make up the fibril before the fiber)

b. Occurs in cytoplasm after terminal amino acids are cleaved

4. Types of Collagena. Type I

i. Fibrillar and associated collagen molecule (type 6)1. Type 6 – collagen regions, in between is a globular domain, which

allows flexibilitya. Purpose of flexibility: strength of fiber and flexibility of

collagen associated proteini. Makes a strong fiber less rigid and more flexible

b. Proteoglycan associates with the fibrils and carries with it the GAGs and water molecules, creating a buffer and gel like substrate for the absorption of force

ii. Boneb. Type II

i. Cartilageii. Associated with non-fibrilar collagen, type IX

1. Type IX has globular repeating units that interact with the fibrilar collagen

a. Has a kink so amino terminus protrudes into ECSb. Organizes collagen fibers in cartilagec. Instead of aligned, they criss-cross one anotherd. More space = more proteoglycans and watere. Provides more flexibility to collagen, unlike bone

5. Diseases/Mutations in Collagena. Hydroxylated states of proline

i. Scurvy1. Caused by a deficiency in vitamin C2. Teeth fall out3. Joints hurt4. All types of collagen break down because the deficiency causes a

decrease in the ability of the cell to hydroxylate prolinea. Less interaction of collagen and the assembly in the

cytoplasm doesn’t take placei. Teeth not connected

b. Type I mutationi. Affects bone tissue

ii. Osteogenesis Imperfecta1. Brittle bones 2. Unbreakable movie

c. Type II mutationsi. Cartilage

ii. Condro displagia1. Abnormal joint formation and structure and function due to

mutation2. Abnormal cartilage formation

d. Type IIIi. ECM

ii. Ailers Danlow Syndrome1. Fragile skin

2. Disruption in basal lamina3. Affects blood vessel strength (weak BVs)4. Hypermobile joints because tendons are very loose5. Recurrent joint dislocation and swelling6. Ruptured blood vessels7. Blister easily

6. Fibronectina. Fibrillar macromoleculeb. Secreted by fibroblasts in the connective tissuec. Made of two polypeptides linked together at COOH terminus by disulfide bondsd. When secreted, has multiple roles because it has different regions that do

different thingsi. Fibrin and heparin binding domains

1. Sites where fibronectin molecules is associate with blood clot processes

2. Helps induce reaction to blood clot formationii. Cell surface receptor binding domain

1. RGD sequence – three amino acidsa. Arginine, glycine, aspartateb. Important for interacting with cells in ECMc. Links with integrin receptors specifically in the PM

i. Bind to fibronectin in the ECMii. If cell is on top of ECM, integrin poke down into ECM

and interact with firboncetin at that particular siteiii. Collagen binding domain

1. Allows fibronectin to interact with collagen and help organize ECMe. Interacts on PM with integrin receptors and the FN out in the environmentf. Integrins transduce signals to the inside of the cells and link to the actin

cytoskeletoni. As integrin binds to actin, actin will grow, so integrins help develop the

structure of the cell1. Cells use these cues to move through environment 2. Allows organization of cytoskeleton3. Allows functioning properly in the tissue types