Extracellular Matrix

Extracellular Matrix

1. The non-cellular component present in all tissues and organs

   • a complex network of proteins and polysaccharides
   • secreted locally by cells that remain closely associated with it
   • provides structural support, adhesive and biochemical signalling support
   • genetic alterations in the ECM results in a wide range of clinical conditions
   • transmits force

2. Connective tissue

   • cellular component
   • acellular component
     • extracellular matrix
       • fibrous component
         • collagen
         • elastin
         • other
       • ground substance (jelly-like component)
         • proteoglycans
         • glycosaminoglycans
         • glycoproteins
         • other

3. Types of extracellular matrix

   • loose networks
     • allows free movement
       • submucosa
   • tightly woven 3D structures
     • resilient properties
       • skin
   • unidirectional alignment
     • tensile strength
       • tendon
   • calcified
     • mechanical properties and strength
       • bone
   • ultra thin tough sheets
     • separation/filter
       • basement membrane

4. Collagen

   • major insoluble fibrous protein in the ECM
   • synthesised as 3 polypeptides
     • triple helix
       • glycine-X-Y
         • X and Y are hydroxyproleins
   • I
     • fibrillar structure
       • dermis, tendons, ligaments and bones
   • II
     • fibrillar structure
       • hyaline cartilage
   • III
     • reticulin
       • liver, bone marrow and lymphoid organs
   • IV
     • sheet/network
       • basement membrane
         • Alport's disease is a genetic condition characterised by kidney disease, hearing loss and eye abnormalities
           • caused by an inherited defect in type IV collagen
   • V
     • link to the basement membrane
       • cornea
   • synthesised as procollagen which is hydroxylated and glycosylated
   • families of collagen
     • fibril forming
       • tensile strength
       • types I, II, III, V, XI, XXIV, XXVII
     • FACIT and related
       • regulate fibril diameter and modify fibril interactions
       • types IX, XII, XIV, XVI, XIX, XX, XXII, XXVI
     • hexagonal network forming
       • molecular sieves that provide planar support for cells
       • types VIII, X
     • endostatin-producing
       • regulators of cell migration and cell signalling
     • anchoring fibrils
       • cell matrix interactions
       • type VII
     • family of type IV
     • type VI bead forming
       • elasticity and long range connectivity
     • transmembrane cell matrix
       • important for interactions
       • type XVII is transmembrane and non-fibrillar (in hemidesmosomes)
   • N-proteinase and C-proteinase cleaves peptides from collagen and it then assembles into collagen fibrils
     • collagen fibrils with lysysl oxidase forms covenant cross-links
   • osteogenesis imperfecta
     • brittle bone disease
       • collagen type 1 related disorder
         • autosomal dominant OI is a COL1A1 or COL1A2 mutation
           • heterotrimeric protomer
         • sillence type
           • I
             • mild-non deformity
           • II
             • perinatal lethal
           • III
             • severely deforming
           • IV
             • moderate deformity
         • Normal: 8xpro-alpha1 + 4xpro-alpha2 = 4 procollagen
         • Mild OI: 4xpro-alpha1 + 4xpro-alpha2 = 2 procollagen
         • more severe OI has 80% glycine missense mutations
           • dominant negative
           • delay in folding results in overmodification (more carbohydrate groups are added to the chain)

5. Elastins

   • structural proteins arranged as fibres
     • structural glycoprotein
   • coated in fibrillin
   • synthesised as tropoelastin
     • undergoes hydroxylation

6. Ground substance

   • fills the gaps between the fibres and the cells
   • glycosaminoglycans
     • link together with a core protein to form even larger molecules called proteoglycans
       • GAGs are the carbohydrate components of proteoglycans
     • mucopolysaccharides
       • chains of repeating disaccharide units
     • hyaluronic acid, chondroitin sulphate, keratan sulphate and heparan sulphate
     • large molecules that attract water
   • good at absorbing water
   • hydrophilic and negatively charged
   • proteoglycans
     • also known as mucoproteins
     • 90-95% carbohydrate
     • protein core + GAG (polysaccharides)
     • examples
       • aggrecan
         • GAG = chondroitin sulphate or keratan sulphate
         • cartilage
         • each proteoglycan is attached to hyaluronic acid to make a massive molecule
         • interacts strongly with collagen type 2 in the ECM of cartilage
       • perlecan
         • GAG = heparan sulphate
         • basement membrane
       • syndecan
         • GAG = chondroitin sulphate or heparan sulphate
         • cartilage
       • decorin
         • chondroitin sulphate or dermatan sulphate
     • made by fibroblasts
       • core protein synthesised on RER and GAGs are added in the Golgi - delivered to extracellular compartments by exocytosis
   • glycoprotein
     • carbohydrate + protein
     • fibrillin
       • controls deposition and orientation of elastin
     • fibronectin
       • organises the ECM and participates in cell attachment to the basement membrane
     • laminin
       • primary organiser of basement layer
     • entactin/nidogen
       • linker role in the basement membrane
     • tenascin
       • linker role in connective tissue

7. Basement membrane

   • lamina lucida
   • lamina densa
   • lamina fibrorecticularis
   • collagen type 4

8. ECM is constantly being made and turned over

   • deposition, modification, degradation
   • MMPs (matrix-metalloproteases)
     • tumour

9. Problems with ECM

   • elastin
     • supravalvular aortic stenosis
   • fibrillin-1
     • Marfan syndrome
   • collagen
     • Elhers-Danlos syndrome
   • keratan sulphate
     • Macular corneal dystrophy
   • perlecan
     • Silverman-handmaker type of dyssegmental dysplasia (DDSH)

10. Early embryo: 80% cells and 20% ECM Adult: 20% cells and 80% ECM

11. ECM absorbs growth factors so that other cells are not overwhelmed with signalling