Mechanisms of ECM formation Flashcards
What is remodelling?
Reorganization or reinovation of existing tissues - causes structural changes in fully differentiated tissues
What happens during tissue repair?
Remodelling replaces the temporary repair structure with a functional new tissue
What can remodelling do to properties of tissues?
Can change the characteristics of a tissue
Result in dynamic equilibrium of a tissue
What is an example of a tissue in which remodelling is essential for the equilibrium of the tissue?
Bone remodelling
Bone tissue is constantly remodelled throughout life and renewed during changes in excercise and growth
What is an example in which remodelling leads to pathology?
Vascular remodelling causes blood vessels to get thicker and less functional in hypertension
Sometimes causes loss of function
What is the key aspect of remodelling?
Restoring function
What are the two things you have to restore in order to restore function of a tissue?
Tissue composition - same cells and matrix components
Tissue structure - cell and matrix arrangement as well as biomechanical properties
What activates tissue remodelling?
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
What are the two types of injury that can occur to the bone?
Mechanical disruptions - fracture
Disease related - inflammation and bacterial infection
What balance does bone remodelling represent?
Balance between:
Bone resorption
Bone ossification
What cells remodel tissues?
Inflammatory cells - secrete proteases that degrade matrix
Fibroblasts - stimulated by cytokies and growth factors
How do fibroblasts remodel the matrix?
Actively remodels the matrix by:
Pulling on it
Secreting proteases
Synthesizing new matrix
ECM can be made by inflammatory cells
TRUE or FALSE
FALSE
Fibroblasts form ECM
How many nuclei do osteoclasts have?
Multinucleated
How many nuclei do osteoblasts have?
Mononucleated
What is the role of osteoclasts?
Destroy the bone matrix
Clean up the wound and destroy unhealthy tissue
So osteoblasts can form new healthy tissue
What is the role of osteoblasts?
Synthesize and mineralise new bone matrix
Steps of bone remodelling following injury
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
Which cells are important in the wound healing process?
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
What is the most significant GF in wound healing?
TGFb
Activate fibroblasts to contract and form new ECM
What are myofibroblasts?
Muscle-y fibroblasts that develop during the conctraction phase
What are the 4 stages of healing?
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
Which cells contract the damaged tissues?
Myofibroblasts
How are myofibroblasts formed?
Fibroblast differentiate into myofibroblasts under the control fo TGFb
Which cells secrete TGFb?
Immune complexes
Describe the structure of myofibroblasts
Made of bundles of filaments of specific isoforms of actin
a-SMA = alpha smooth muscle actin
What is the role of myofibroblasts?
Contractile cytoskeleton
Grab the matrix and mechanically move it close to the wound site
Also secrete collagen and fibronectin matrix
Which matrix components are important in remodelling?
Collagens
Elastins
GAGs
Proteoglycans
Fibronectin
Laminin
What is the most abundant protein in the body?
Collagen
What are the 4 major types of collagen?
Collagen I - all connective tissue
Collagen II - cartilage
Collagen III - cartilage
Collagen IV - basement membrane
What is the role of elastins?
Elasticity
Load bearing rebound
What is the role of GAGs?
Interact with collagen and elastin
What is the structure of PGs?
GAGs on protein core
What is the role of PGs?
Highly hydrated - osmotic gradient created by GAGs
Serves as lubricants or cushions
What is Fibronectin?
Multi adhesive protein binding colllagen
What is Laminin?
Multi adhesive protein fonu in basal lamina
What are types of enzymes that degrade ECM?
MMPs
Cathepsin K
ADAMT
What are MMPs?
Matrix metalloproteinases
Main family that degrade components of the matrix
Secreted by inflammatory cells, fibroblasts and specialised cells
Which specialised cells secrete MMPs?
Chondrocytes
Osteoclasts
What are TIMPs?
Inhibitors of MMPs
What does TIMP/MMP ration determine?
Whether tissue will be degraded or remodelled
What does Cathepsin K degrade?
Bone elastin and collagen
What does ADAMT degrade?
Cartilage matrix - aggrecan units
What is the biological consequence of matrix degradation?
Release of matrix-bound GF and peptides
Nature of factors released can determine whether tissue is remodelled or broken down
What is mechanosensing?
Link between mechanical tension and matrix remodelling
How do cells sense tension?
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
What are cadherins?
Cell surface receptors that permit cell to attach to each other
So the forces can be transmitted from one cell to another
What is the difference between integrins and cadherins?
Integrins relays stress from outside to inside cytoskeleton
Cadherins relays stress from cell to cell
How is mechanical stress converted into a signal the cell understands?
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
Examples of pathologies that arise if remodelling goes wrong
Tissue lose function if remodelling goes wrong - too stiff/ soft
Osteoporosis - too much degradation
Osteoarthritis
Hypertension
Paget’s bone disease - bone overgrowth
