OMG Lecture 40: The extracellular matrix Flashcards
Tuesday 21st January 2025
Is it true that eukaryotic cells exist in a physical environment?
Yes. (Cell-cell junctions + Extracellular Matrix)
Is it true that that the extracellular matrix is a major product of the secretory pathway?
Yes
Why is the extracellular matrix important?
- Holds the cells together and anchors their cytoskeleton
- Provides the environment where cells interact or move
- The matrix composition is different in different tissues
- In animals, it’s made of proteins and polysaccharides
- Present in dense connective tissues (bone/teeth, tendons, exoskeleton of arthropods, shells of molluscs)
(The matrix is thick and has a primary mechanical role
)
- And in lose connective tissues (over epithelium, gut, skin, eyes - cornea)
(The matrix is thin, cells are connected by cell-cell junctions ; Links cytoskeleton to extracellular structures
)
What does the extracellular matrix do?
- Scaffolding role supporting cells (as provides strength, elasticity, turgor).
- Influences cell behaviour, e.g. survival, development, migration, shape, proliferation, and function.
What is turgor?
The internal ‘tension’ in a tissue
In isotonic conditions…
flaccid
In hypotonic conditions…
Turgid
In the ECM, what does the turgor help to do?
In the ECM, it helps absorb impact and provides scaffolding for the cells in tissues
Where are ECM molecules produced?
Locally
ECM molecules are secreted by fibroblasts in…
Secreted by fibroblasts in loose Connective tissue
ECM molecules are secreted by osteoblasts in…
Secreted by osteoblasts in bone
ECM molecules are secreted by chondrocytes in…
Secreted by chondrocytes in cartilage
Spaces around cells are filled with secreted molecules that form a gel…
POLYSACCHARIDES
Glycosaminoglycans (GAG)/proteoglycans (e.g. hyaluronan TURGOR, dermatan sulfate TISSUE DEVELOPMENT)
PROTEINS
Fibrous proteins (e.g. collagen STRENGTH, elastin ELASTICITY)
Glycoproteins (fibronectin REGENERATION)
Does turgor help plant cells to absorb impact?
Yes
What are Glycosaminoglycan (GAG) chains?
- Glycosaminoglycan (GAG) chains are repeated units of negatively charged (-) disaccharides that form very long linear chains.
- They attract cations (Na+) causing large amounts of water to be sucked into the matrix - hydration. This creates turgor.
Hyaluronan (hyaluronic acid)…
Resists compressive forces in tissues and joints
Dermatan sulfate…
- Assembly of collagen
- Essential for tissue development
What are the other main types of polysaccharides/ Glycosaminoglycans (GAGs) in the ECM?
- Heparan sulfate
- Keratan sulfate
Is it true that all Glucosaminoglycans and proteoglycans are synthesised in and secreted by cells that are within the ECM?
Yes
Proteoglycans…
- PROTEIN TRANSLOCATION in the ER
- Addition of the precursor oligosaccharide in the ER
- SECRETORY PATHWAY
- Modification of the oligosaccharide chain in the Golgi
- Exocytosis or anchoring in plasma membrane (syndecans)
Proteoglycans are translocated into the ER and checked for correct folding, before entering the secretory pathway.
Proteoglycans are translocated into the ER and checked for correct folding, before entering the secretory pathway.
Give an example of proteoglycans
Syndecans
What does syndecan do?
Regulates cell-matrix adhesions and influences cell behaviour
What are syndecans?
Syndecans are transmembrane proteoglycans, meaning they span the cell membrane and help connect the cell to its environment.
What are the 3 main domains that syndecans consist of?
- C-terminal cytoplasmic domain (CD) – Inside the cell, helps with signaling.
- Transmembrane domain (TM) – Anchors the syndecan in the cell membrane.
- Extracellular domain (ED) – Extends outside the cell and interacts with molecules in the ECM.
What chains do syndecans have attached to them?
Syndecans have heparan sulfate (HS) chains attached to them.
What are heparan sulfate (HS) chains?
HS chains are a type of glycosaminoglycan (GAG) that interacts with various molecules in the ECM.
What’s the function of syndecans?
- Act as co-receptors or activators
- The HS chains can bind to:
- Growth factors (e.g., FGF – Fibroblast Growth Factor), enhancing their signaling.
- ECM components (e.g., fibronectin, collagen) to help cell adhesion and communication.
- Also, signal transduction
How can syndecans carry out signal transduction?
- The TM (transmembrane) and ED (extracellular) domains help transmit signals from the ECM to the cell.
- This influences cell behavior, differentiation, and response to the environment.
Summary of syndecans
- Syndecans are transmembrane proteoglycans that link cells to the ECM.
- They have heparan sulfate (HS) chains, which help in binding growth factors and ECM molecules.
- They function as co-receptors and are involved in cell signaling.
- The extracellular matrix is dynamic, influencing cell behavior and communication.
The extracellular matrix (ECM) is not just a structural material but plays an active role in cell communication and regulation!
The extracellular matrix (ECM) is not just a structural material but plays an active role in cell communication and regulation!
Describe the ECM composition
- Diverse components, different pore sizes, and molecule charges
- Different hydration levels, different cell turgor and ECM transport
Are the ECM components very big?
Yes
Components of the ECM are polysaccharides AND proteins
Components of the ECM are polysaccharides AND proteins
What is an example of a fibrous ECM protein?
Collagen
What pervcentage of the protein in the body is collagen
25%
How many known types of collagen are there?
More than 20
How many amino acids long is collagen?
300aa long
Is it true that in the ER, there are multiple modifications as the collagen is being translated?
Yes
In the ER, what modifications are made to collagen as collagen is being translated?
- Modifications improve the solubility of the pro-collagen
- About 50% of the proline residues are hydroxylated (-OH) by collagen prolyl-hydroxylases - this requires vitamin C
- Specific lysine residues are hydroxylated– this also requires vitamin C
- The C-terminal domains are N-glycosylated
- And, mostly in the Golgi, some of the hydroxylysyls are O - glycosylated by addition of galactose or a glucose-galactose disaccharide.
In the ER, how do the C terminal domains of monomers trimerise ?
Via disulfide bonds
IS it true that winding produces a stiff triple stranded helical structure with highly soluble N and C termini/
Yes
What is Hsp47?
a collagen-specific chaperone that aids the winding of collagen
What are the functions of the N and C terminal propeptides?
- One other function of the N and C propeptides is to keep the trimers apart: this stops them forming fibrils …
… until late in the secretory pathway, when the propeptides are removed, forming tropocollagen
How do fibrils form prior to secretion?
- Individual tropocollagens are crosslinked (covalent intra- and inter-molecular covalent cross-linking between hydroxylysyls) to form fibrils.
Describe fibripositors…
- Fibripositors are tubular extensions at the plasma membrane that accept GPCs (Golgi to PM carriers) containing collagen
- A closed fibripositor opens by fusing with the PM, and the collagen fibril is extruded out of the cell
- The fibrils line up in the ECM, in register
How is collagen arranged in the skin?
- Collagen fibrils in skin are arranged like wickerwork:
- This is (partly) why (young) skin springs back into shape … but with age … (oh, dear)
How is collagen arranged in the bone?
- Collagen fibrils in bone have a “plywood” arrangement that does not allow stretching
- This is (partly) why bone is stiff, strong, tough and lightweight (it is also helped by mineralisation)
How is collagen arranged in tendons?
- And in tendons, collagen fibrils aggregate to form a fibre (a supercable!) …
- This is why tendons can be stretched without breaking
What is a tendon?
A tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone.
Why is collagen highly processed in the ER and the golgi?
To make the collagen more soluble and to prevent the aggregation of monomers.
Where do PM carriers take collagen>
from the golgi to the EM
How can collagen form so many differnt arrangemets?
Because its fibrils are easily arranegd
What makes up the basement lamellae?
- Type IV collagen forms X-shaped complexes that combine to form a network
- Laminin: cross shaped
- Perlecan: long, snaky proteoglycans
- Plus smaller Proteoglycans that fill in the spaces
What are basement lamellae?
Basement lamellae are dense sheets of interacting proteins.
What does the hydroxylation of collagen require?
Vitamin C
What happens with reduced collagen hydroxylation?
With reduced hydroxylation, collagen is mis-formed: connective tissue problems arise, such as scurvy
What deficiency causes scurvy?
Vitamin C
Name some collagen disorders
- Osteogenesis imperfecta/brittle bone disease
- Type I collagen alteration
- Schmidt-type chondrodysplasias
- Type X collagen alteration
- Ehlers-Danlos syndromes
-
Describe elastin
- A hydrophobic elastic protein, with extensive crosslinks, highly prevalent in the ECM of arteries (50% dry weight of the aorta).
- Gives tissues their elasticity.
Is elastin a fibrous protein?
Yes
Can fibronectin be described as ‘sticky’?
Yes
Fibronectin has multiple domains for binding to….
- to itself
- to other ECM molecules
- and also to integrins/cell receptors
How does the cytoskeleton interact with fibronectin to produce tension?
Since the cytoskeleton is (indirectly) connected to ECM molecules, the cell can contract and pull on the fibronectin in the matrix to create tension
Is the basal lamina a very important extracellular matrix?
Yes
Describe the basal lamina
- Basal lamina is a specialized type of ECM also known as basement membrane
- 40-120nm thick and lies beneath epithelial cells
- Allows mechanical connection
- Is synthesized by cells around it
- Contains glycoproteins laminin, type IV collagen and nidogen
Is it true that the basal lamina allows mechanical connection of cells in the connective tissue?
Yes
Is it true that cells degrade the ECM matrix as well as making it?
Yes
Describe how cells degrade the ECm
- When cells divide they need to stretch out (which requires them to cut into the ECM)
- When cells migrate through connective tissue localised degradation of ECM is required e.g. white blood cells moving through the basal lamina of a blood vessel to get to tissues in response to infection
- Matrix degradation is also needed in tissue repair and tissue remodelling
- The proteases responsible (matrix metalloproteases and serine proteases) must be tightly controlled if the body isn’t to collapse!!
- This is achieved by local activation, confining these enzymes to cell surfaces, and by secreting potent inhibitors
The ECM and cancer
- The tight binding of the cytoskeleton to the ECM means that cells can control the shape (and content) of the ECM: however, that tight binding implies that for cell movement and division, cells must let go of and degrade the ECM
- Cancer cells often down-regulate fibronectin, so they have weak contacts with the ECM: this makes it easier to divide in an uncontrolled manner, and allows cancerous cells to migrate more easily: it permits metastasis
- The matrix metalloproteinases are also required for tumour invasion and neoangiogenesis as well as metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy
SUMMARY
- Cells in connective tissues are embedded in an ECM. ECM molecules may influence these cells (e.g. activating signalling pathways)
- Glycosaminoglycans and proteoglycans form hydrated gels and provide turgor, support and a medium for cell migration
- Fibres strengthen and shape the matrix and provide surfaces for cells to stick to (next lecture)
- Fibres are composed of rope-like (or mesh-like) collagens and stretchy elastins
- Sticky fibronectins help organise the matrix molecules and help bind cells
- The cytoskeleton (next lecture) indirectly connects with ECM molecules and influences the way these are organised
- Local cells can also degrade ECM components in a regulated manner
