Extracellular Matrix
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What is the extracellular matrix (ECM)?
A complex network of extracellular macromolecules that provides structural support to tissues and influences cell behaviour.
What are the three main classes of ECM macromolecules?
Fibrous proteins, non-collagen glycoproteins and glycosaminoglycans (GAGs).
What are the major fibrous proteins of the ECM?
Collagens.
What is an important example of a non-collagen glycoprotein in the ECM?
Fibronectin.
What are glycosaminoglycans (GAGs)?
Highly charged polysaccharides that often bind to proteins to form proteoglycans.
What are the major functions of the extracellular matrix?
Provide structural support, determine tissue mechanical properties, regulate cell growth and adhesion, influence differentiation and support tissue development and organogenesis.
Why is the ECM not simply an inert scaffold?
It actively influences cell behaviour, growth, migration, survival and differentiation.
How does the ECM influence tissue mechanical properties?
The composition and organisation of ECM molecules determine tissue strength, flexibility, elasticity and resistance to compression.
Why is the ECM essential during embryonic development?
It guides cell migration, tissue organisation and organ formation.
Which cells are the principal producers of connective tissue ECM?
Fibroblasts.
What is the role of fibroblasts in the ECM?
They synthesise, secrete and remodel extracellular matrix components.
How do cells physically interact with the ECM?
Through cell-surface receptors such as integrins.
Why can different tissues have very different properties despite containing collagen?
Different collagen types, fibre orientations and additional ECM components generate tissue-specific mechanical properties.
How does collagen contribute to the properties of tendon?
It provides high tensile strength while maintaining flexibility.
How does collagen contribute to the properties of bone?
It contributes to a dense framework that supports tissue hardening and strength.
How does collagen contribute to the properties of cartilage?
It helps create a resilient matrix that absorbs compressive forces.
What is collagen?
A family of fibrous extracellular proteins that are the major structural components of connective tissues.
How widely distributed are collagens?
They are found in all multicellular organisms.
What proportion of total mammalian protein is collagen?
Approximately 25%.
Why are collagens considered the most abundant proteins in mammals?
They account for roughly one quarter of total protein mass.
Which cells continuously remodel collagen in tissues?
Resident fibroblasts.
Why is collagen remodelling important?
It allows tissues to adapt to injury, growth and changes in mechanical stress.
How are collagen fibrils arranged in skin?
In successive layers with fibres oriented in different directions.
Why are collagen fibres arranged in multiple directions in skin?
To allow resistance to tensile forces from many directions.
What is tensile force?
A pulling or stretching force applied to tissue.
How do collagen fibrils help tissues resist tensile force?
Their organisation distributes stress and reduces the risk of tissue tearing.
Which tissues were highlighted as having layered collagen arrangements?
Skin, bone and cornea.
What is the characteristic amino-acid sequence repeat found in collagens?
Gly-X-Y.
Which amino acid is commonly found at the X position of collagen repeats?
Proline.
Which amino acid is commonly found at the Y position of collagen repeats?
Hydroxyproline.
Why is glycine required at every third residue in collagen?
Glycine is small enough to occupy the crowded interior of the triple helix.
Why would larger amino acids disrupt collagen structure?
They would not fit within the central core of the triple helix.
What is the fundamental structural unit of fibrillar collagen?
A triple helix formed from three alpha chains.
What is an alpha chain in collagen?
A polypeptide chain approximately 1000 amino acids long that forms a left-handed helix.
How is the collagen triple helix formed?
Three alpha chains wrap around each other to form a stiff right-handed triple-helical structure.
Why is the collagen triple helix mechanically strong?
The tightly packed glycine-rich core and extensive intermolecular interactions provide stability.
What is hydroxyproline?
A modified form of proline commonly present in collagen.
Why is hydroxyproline important in collagen?
It contributes to stability of the triple-helical structure.
How many genes encode collagens in humans according to the lecture?
Approximately 42 genes.
How many different collagen types arise from these genes?
Approximately 28 collagen types.
How are collagen types conventionally named?
Using Roman numerals.
What is a heterotrimeric collagen?
A collagen triple helix composed of more than one alpha-chain type.
What is an example of a heterotrimeric collagen?
Type I collagen.
What is the molecular composition of type I collagen?
[α1(I)]₂[α2(I)].
What does [α1(I)]₂[α2(I)] indicate?
Two α1(I) chains and one α2(I) chain form the type I collagen triple helix.
What is a homotrimeric collagen?
A collagen triple helix composed of three identical alpha chains.
What is an example of a homotrimeric collagen?
Type II collagen.
What is the molecular composition of type II collagen?
[α1(II)]₃.
What is the molecular composition of type III collagen?
[α1(III)]₃.
Why can collagen molecules exhibit enormous structural diversity?
Multiple collagen genes and alpha-chain combinations generate many distinct collagen types.
What is the purpose of collagen biosynthesis?
To generate stable extracellular collagen fibres capable of supporting connective tissues.
Why are collagen fibres stronger than individual collagen molecules?
Multiple collagen molecules assemble into larger fibrils and fibres with extensive cross-linking.
What are collagen cross-links?
Covalent bonds that connect collagen molecules together.
Why is collagen cross-linking important?
It increases tensile strength and structural stability.
Which amino acids participate in collagen cross-link formation?
Lysine and hydroxylysine.
How does collagen cross-linking affect tissue mechanics?
Greater cross-linking generally increases tissue strength and stiffness.
Does collagen cross-linking remain constant throughout life?
No, the degree and type of cross-linking change with age.
Why do different tissues possess different collagen cross-linking patterns?
Different tissues require distinct mechanical properties.
What are Ehlers-Danlos syndromes (EDS)?
A group of inherited connective-tissue disorders caused by defects affecting collagen structure or function.
What are the classical clinical features of Ehlers-Danlos syndromes?
Hyperextensible skin and hypermobile joints.
Why are joints hypermobile in Ehlers-Danlos syndrome?
Defective collagen weakens connective tissues that normally stabilise joints.
Why is skin unusually stretchy in Ehlers-Danlos syndrome?
Abnormal collagen reduces tensile strength and increases tissue laxity.
Which collagen genes were highlighted in EDS?
COL5A1 and COL5A2.
How do collagen mutations produce Ehlers-Danlos syndrome?
Abnormal collagen weakens connective tissues and alters tissue mechanics.
Why is EDS considered a connective-tissue disease?
Collagen is a major structural component of connective tissues throughout the body.
What is fibrosis?
Pathological accumulation of excessive extracellular matrix, particularly collagen.
What is the key pathological feature of fibrotic disease?
Excess extracellular matrix deposition.
Why can fibrosis impair organ function?
Excess ECM replaces normal tissue architecture and restricts organ function.
What is liver fibrosis commonly called in advanced disease?
Cirrhosis.
What is the major ECM abnormality in cirrhosis?
Excess collagen deposition within the liver.
What is idiopathic pulmonary fibrosis?
A fibrotic lung disease characterised by excessive ECM accumulation and progressive loss of lung function.
How can excessive collagen deposition affect the lungs?
It makes lung tissue less compliant and impairs gas exchange.
How can excessive collagen deposition affect the kidneys?
It disrupts normal filtration structures and contributes to renal dysfunction.
Why is fibrosis often progressive?
Continuous ECM deposition further distorts tissue architecture and promotes additional dysfunction.
What is the opposite pathological problem to fibrosis?
Excessive ECM degradation or loss.
What disease was highlighted as an example of excessive ECM loss?
Rheumatoid arthritis.
Why is ECM balance important for tissue health?
Both excessive deposition and excessive degradation can impair normal tissue function.
What are fibril-associated collagens?
Collagens that associate with the surface of collagen fibrils rather than forming the main fibrils themselves.
What is the primary function of fibril-associated collagens?
To regulate collagen fibril organisation, spacing and interactions with other extracellular matrix components.
Why are fibril-associated collagens important despite being less abundant than fibrillar collagens?
They help organise collagen networks and influence tissue architecture.
What is the basement membrane?
A specialised sheet-like extracellular matrix that underlies epithelia and surrounds certain cell types.
Where is the basement membrane found?
Beneath epithelial cells and around structures such as muscle cells, blood vessels and nerves.
What are the major functions of the basement membrane?
Structural support, tissue compatmentalisation, cell adhesion, filtration and regulation of cell behaviour.
Why is the basement membrane important for epithelial tissues?
It provides mechanical support and anchors epithelial cells to the underlying connective tissue.
How does the basement membrane influence cell behaviour?
It provides biochemical and mechanical cues that affect cell survival, differentiation, migration and polarity.
What is the major collagen of basement membranes?
Type IV collagen.
Why is type IV collagen different from fibrillar collagens?
It forms mesh-like networksrather than long rope-like fibrils.
What mechanical advantage does the type IV collagen network provide?
It creates a flexible sheet capable of supporting tissues while allowing selective permeability.
What is the principal structural role of type IV collagen in basement membranes?
To form a supporting scaffold-like network.
Which disease discussed in the lecture is caused by mutations in type IV collagen genes?
Alport syndrome.
What is Alport syndrome?
An inherited disorder caused by mutations affecting type IV colagen in basement membranes.
Why does Alport syndrome commonly affect the kidneys?
The glomerular basement membrane depends heavily on normal type IV collagen networks for filtration.
How does abnormal type IV collagen affect kidney filtration?
It weakens the glomerular basement membrane and impairs normal filtration function.
Which basement membrane structure is particularly important in Alport syndrome?
The glomerular basement membrane of the kidney.
What are characteristic clinical manifestations of Alport syndrome?
Progressive kidney disease, hearing loss and ocular abnormalities.
Why can hearing be affected in Alport syndrome?
Type IV collagen is also important in specialised basement membranes of the inner ear.
Why can eye abnormalities occur in Alport syndrome?
Type IV collagen contributes to basement membrane structures within the eye.
What is the glomerular basement membrane?
A specialised basement membrane that forms a key component of the kidney filtration barrier.
What is one major function of the glomerular basement membrane?
To permit filtration of plasma while restricting passage of large molecules and cells.
What is diabetic nephropathy?
Kidney disease caused by chronic diabetes-associated damage to renal structures.