Mechanisms of ECM formation

Question 1

What is remodelling?

Answer 1

Reorganization or reinovation of existing tissues - causes structural changes in fully differentiated tissues

Question 2

What happens during tissue repair?

Answer 2

Remodelling replaces the temporary repair structure with a functional new tissue

Question 3

What can remodelling do to properties of tissues?

Answer 3

Can change the characteristics of a tissue

Result in dynamic equilibrium of a tissue

Question 4

What is an example of a tissue in which remodelling is essential for the equilibrium of the tissue?

Answer 4

Bone remodelling

Bone tissue is constantly remodelled throughout life and renewed during changes in excercise and growth

Question 5

What is an example in which remodelling leads to pathology?

Answer 5

Vascular remodelling causes blood vessels to get thicker and less functional in hypertension

Sometimes causes loss of function

Question 6

What is the key aspect of remodelling?

Answer 6

Restoring function

Question 7

What are the two things you have to restore in order to restore function of a tissue?

Answer 7

Tissue composition - same cells and matrix components

Tissue structure - cell and matrix arrangement as well as biomechanical properties

Question 8

What activates tissue remodelling?

Answer 8

Normal physiology and growth - bones need remodelling to maintain homeostasis of the bone -> bone has to grow with the body

Exercise - the more you exercise the muscle, bone becomes stronger

Repair after injury

Question 9

What are the two types of injury that can occur to the bone?

Answer 9

Mechanical disruptions - fracture

Disease related - inflammation and bacterial infection

Question 10

What balance does bone remodelling represent?

Answer 10

Balance between:

Bone resorption

Bone ossification

Question 11

What cells remodel tissues?

Answer 11

Inflammatory cells - secrete proteases that degrade matrix

Fibroblasts - stimulated by cytokies and growth factors

Question 12

How do fibroblasts remodel the matrix?

Answer 12

Actively remodels the matrix by:

Pulling on it

Secreting proteases

Synthesizing new matrix

Question 13

ECM can be made by inflammatory cells

TRUE or FALSE

Answer 13

FALSE

Fibroblasts form ECM

Question 14

How many nuclei do osteoclasts have?

Answer 14

Multinucleated

Question 15

How many nuclei do osteoblasts have?

Answer 15

Mononucleated

Question 16

What is the role of osteoclasts?

Answer 16

Destroy the bone matrix

Clean up the wound and destroy unhealthy tissue

So osteoblasts can form new healthy tissue

Question 17

What is the role of osteoblasts?

Answer 17

Synthesize and mineralise new bone matrix

Question 18

Steps of bone remodelling following injury

Answer 18

Input from outside triggers remodeling

Osteoclasts are recruited

Move through lining of bone cells

Osteoclasts digests the tissues

Osteoblasts move into hole of digested tissue and fill it with temporary tissue

Further matrix synthesis and mineralisation creates new tissue

Bone formation finishes

Osteoblasts will enter quiescent state and form lining bone cells

Question 19

Which cells are important in the wound healing process?

Answer 19

Macrophages and fibroblasts - release GF and cytokines

Fibrin clot - clot skin temporarily and recruits more inflammatory cells via release of cofactors

Fibrin - contains immune complexes that release GF

Question 20

What is the most significant GF in wound healing?

Answer 20

TGFb

Activate fibroblasts to contract and form new ECM

Question 21

What are myofibroblasts?

Answer 21

Muscle-y fibroblasts that develop during the conctraction phase

Question 22

What are the 4 stages of healing?

Answer 22

Hemostasis - fibrin clots and blocks the wound

Inflammatory phase - cytokines and GF are released by WBC due to damage

Proliferative phase - recruitment of fibroblasts and WBC

Wound contraction and matrix remodelling - get rid of replacement tissue. Myofibroblasts contract the tissue actively and secrete more ECM

Question 23

Which cells contract the damaged tissues?

Answer 23

Myofibroblasts

Question 24

How are myofibroblasts formed?

Answer 24

Fibroblast differentiate into myofibroblasts under the control fo TGFb

Question 25

Which cells secrete TGFb?

Answer 25

Immune complexes

Question 26

Describe the structure of myofibroblasts

Answer 26

Made of bundles of filaments of specific isoforms of actin a-SMA = alpha smooth muscle actin

Question 27

What is the role of myofibroblasts?

Answer 27

Contractile cytoskeleton Grab the matrix and mechanically move it close to the wound site Also secrete collagen and fibronectin matrix

Question 28

Which matrix components are important in remodelling?

Answer 28

Collagens Elastins GAGs Proteoglycans Fibronectin Laminin

Question 29

What is the most abundant protein in the body?

Answer 29

Collagen

Question 30

What are the 4 major types of collagen?

Answer 30

Collagen I - all connective tissue Collagen II - cartilage Collagen III - cartilage Collagen IV - basement membrane

Question 31

What is the role of elastins?

Answer 31

Elasticity Load bearing rebound

Question 32

What is the role of GAGs?

Answer 32

Interact with collagen and elastin

Question 33

What is the structure of PGs?

Answer 33

GAGs on protein core

Question 34

What is the role of PGs?

Answer 34

Highly hydrated - osmotic gradient created by GAGs Serves as lubricants or cushions

Question 35

What is Fibronectin?

Answer 35

Multi adhesive protein binding colllagen

Question 36

What is Laminin?

Answer 36

Multi adhesive protein fonu in basal lamina

Question 37

What are types of enzymes that degrade ECM?

Answer 37

MMPs Cathepsin K ADAMT

Question 38

What are MMPs?

Answer 38

Matrix metalloproteinases Main family that degrade components of the matrix Secreted by inflammatory cells, fibroblasts and specialised cells

Question 39

Which specialised cells secrete MMPs?

Answer 39

Chondrocytes Osteoclasts

Question 40

What are TIMPs?

Answer 40

Inhibitors of MMPs

Question 41

What does TIMP/MMP ration determine?

Answer 41

Whether tissue will be degraded or remodelled

Question 42

What does Cathepsin K degrade?

Answer 42

Bone elastin and collagen

Question 43

What does ADAMT degrade?

Answer 43

Cartilage matrix - aggrecan units

Question 44

What is the biological consequence of matrix degradation?

Answer 44

Release of matrix-bound GF and peptides Nature of factors released can determine whether tissue is remodelled or broken down

Question 45

What is mechanosensing?

Answer 45

Link between mechanical tension and matrix remodelling

Question 46

How do cells sense tension?

Answer 46

Integrin links ECM to cell cytoskeleton Forces are tranmitted from outside the cell to the inside Integrin relays mechanical stress and relays the information to the actin or intermediate filament cytoskeleton

Question 47

What are cadherins?

Answer 47

Cell surface receptors that permit cell to attach to each other So the forces can be transmitted from one cell to another

Question 48

What is the difference between integrins and cadherins?

Answer 48

Integrins relays stress from outside to inside cytoskeleton Cadherins relays stress from cell to cell

Question 49

How is mechanical stress converted into a signal the cell understands?

Answer 49

Mechanical signals is picked up by integrins/ cadherins Converted to biochemical signals inside the cells This triggers signal transduction cascades that lead to gene expression Turn cellls more contractile and start formation of cytokines Also determines matrix components

Question 50

Examples of pathologies that arise if remodelling goes wrong

Answer 50

Tissue lose function if remodelling goes wrong - too stiff/ soft Osteoporosis - too much degradation Osteoarthritis Hypertension Paget's bone disease - bone overgrowth