Special T

• Extracellular matrix


  Provides a chemical and mechanical structure
• Extracellular matrix


  • Diverse characteristics include stiffness and composition
  • Plays an important role in development, in inflammatory states and in the spread of cancer cells
• 3 Major Classes of extracellular matrix


  • Structural Proteins
  • Specialized Proteins
  • Glycosaminoglycans and Proteoglycans
• Structural Proteins


  Collagen, Elastin, Fibrillin

  
• Specialized Proteins


  Fibronectin, Laminin
• Collagen


  • Most abundant structural protein in all animals
  • In humans, it comprises one-third of the total protein, accounts for three-quarters of the dry weight of skin, and is the most prevalent component of the extracellular matrix (ECM)
  • Approximately 1000 amino acids
• Collagen


  • The repeating triplet (Glycine, Hydroxyproline, Proline) is the absolute requirement for the formation of the triple helix
  • Glycine – smallest and simplest amino acid is at every 3rd position of the triple helical portion of the chain and this is a striking characteristic of collagen
  • Proline and Hydroxyproline – confer the rigidity of the collagen molecule
  • Hydroxylation of Proline residues increases the thermal stability of the triple helices

  
• Types of Collagen


  • Type I - Fibrillar, abundant in dermis, bone, tendon, ligament
  • Type II - Fibrillar, abundant in cartilage, vitreous
  • Type III - Fibrillar, abundant in skin, blood vessels, intestine
  • Type IV - Network, abundant in basement membranes
  • Type VII - Anchoring fibrils, abundant in dermis, bladder
  • Type XIII - MACIT, abundant in endothelial cells, dermis, eye, heart
  • Type XVIII - MULTIPLEXIN, abundant in basement membrane, liver

  
• Remember the acronym SCAB: Type I Collagen – abundant in Skin, Sclera and Bone, Type II Collagen – abundant in Cartilage, Type III Collagen – abundant in Arteries and Skin, Type IV Collagen – abundant in Basement membrane

  
• Other important Collagen: Type VII – an anchoring fibril, Type XVIII – an endostatin which is an inhibitor of angiogenesis

  
• Collagen Synthesis


  1. Hydroxylation

  2. Glycation

  3. Disulfide Bonding

  4. Triple Helix Formation

  5. Excision of Collagen

  6. Oxidative Deamination of Collagen Fibril

  7. Formation of Aldo Condensation Crosslinks

  
• Intracellular steps in collagen synthesis: Cleavage of signal peptide, Hydroxylation of prolyl residues and some lysyl residues, Formation of intrachain and interchain S-S bonds in extension peptides, Formation of triple helix

  
• Extracellular steps in collagen synthesis: Cleavage of amino and carboxy terminal propeptides, Assembly of collagen fibers in quarter-staggered alignment, Oxidative deamination of amino groups of lysyl and hydroxylysyl residues to aldehydes, Formation of intra- and interchain cross links via Schiff bases and aldol condensation products

  
• Collagen Diseases - Increased Collagen Production


  • Keloid
  • Lung-pulmonary fibrosis
  • Liver cirrhosis

  
• Collagen Diseases - Decreased Collagen Production


  • Ehlers-Danlos syndrome
  • Osteogenesis Imperfecta
  • Scurvy

  
• For decreased collagen production diseases, it can be due to mutation on collagen, ↓ enzymes, or ↓ cofactors. For increase collagen production diseases, it can cause keloid, lung-pulmonary fibrosis or liver cirrhosis.

  
• Keloids have 14 times greater prolyl hydroxylase activity and 14 times faster collagen synthesis compared to normal scars. Keloids have Collagen Type III and Chondroitin 4-Sulfate which cannot be found in normal scars. Keloids have immature collagen while Normal scars have mature collagen.

  
• Hypertrophic scar


  The scar formed here can be seen on the site of injury, it does not go beyond the site of injury. They also have ↑ collagen synthesis, but their collagenase activity is normal (similar with a normal scar)
• Keloid scar


  The scar formed extends from the site of injury since it has immature collagen
• Collagen Defects in Disorders


  • Osteogenesis Imperfecta Type 1 - ↓ Synthesis of Type 1 collagen
  • Scurvy - ↓ Hydroxylation
  • Atopic Dermatitis - Mutation in Collagen XXIX
  • Ehlers-Danlos Syndrome - Poor secretion, premature degradation of Type III collagen
  • Epidermolysis Bullosa - Mutation in Type 7 collagen
  • Ehlers-Danlos VI - ↓ hydroxylysine in Types 1 and 3 collagen
  • Ehlers-Danlos VII - Type 1 procollagen accumulation, N-terminal propeptide not cleaved
  • Menke's Disease - Lysyl oxidase

  
• Osteogenesis Imperfecta


  Decreased Collagen Type I, also called "Brittle Bone Disease"
• Osteogenesis Imperfecta


  • Blue Gray Sclera (pathognomonic sign), S-curved scoliosis, High probability of bone fracture, Teeth are brittle
• Ehlers-Danlos Syndrome


  Mutation of Collagen Type I to X
• Ehlers-Danlos Syndrome


  • Abnormal wound healing, Easy bruising, Hyperelasticity of skin, Hypermobility of joints, Hyperextensibility of joints
• Ehlers-Danlos Type 4


  Vascular type, the most serious type because it has the tendency to have rupture arteries, Skin is thin, Easy bruisability, Abnormality in Type 3 Collagen
• Ehlers-Danlos Type 6


  Kyphoscoliotic type, secondary to ↓ lysyl hydroxylase, Hyperextensibility, Hyperelasticity, Hypermobility
• Ehlers-Danlos Type 7


  Secondary to ↓ in procollagen peptidase, Hyperextensibility, Hypermobility, Can rotate head 360o
• Diagnosis for Ehlers-Danlos Syndrome: Beighton Score + Brighton Criteria
• Epidermolysis Bullosa


  Mutation in Collagen Type VII, No production of Anchoring fibrils

  
• Epidermolysis Bullosa


  • Bullae – fluid present between the epidermis and dermis, Epidermis detaches easily from the dermis
• Achondrodysplasia


  Genetic defect of Collagen Type II and X

  
• Achondrodysplasia


  • Short stature, Larger head/forehead, Normal-sized torso, Shorter extremities
• Dwarfism


  Decrease or Low Growth Hormones
• Dwarfism


  • Short stature but has symmetrical growth, Head proportional to extremities
• Menke's Disease


  Defect in Copper transport
• Menke's Disease


  • No lysyl oxidase, Twisted hair and Hypopigmented hair, Neurological symptoms and decreased muscle tone
• Elastin


  Similar synthesis process as Collagen

  
• Comparison of Collagen and Elastin

  
• Cutis Laxa


  Deletion of Elastin gene or Fragmentation/Decrease in Elastin
• Cutis Laxa


  • Looks old for their age, Sagging of skin