L9: Extracellular Matrix Flashcards
Functional attributes of ECM
- Structure
- Defense/protection/barrier
- Nutrition (diffusion of metabolic fuels)
- Diffusion of gases, molecules and ions
- Cell growth and survival
- Cell migration
- Lubrication
What is granulation tissue?
- Tissue that is the hallmark of tissue repair
Basic structures of the ECM
- ) Ground substance
- Glycosaminoglycans/mucopolysaccharides
- Proteoglycans
- Multiadhesive Glycoproteins
- Water - ) Fibers/CT
- Collagen
- Reticular (type III collagen)
- Elastic
Characteristics of ground substance. Function
Characteristics:
- Amorphous intercellular material that is transparent, colorless and homogenous, hydrated, fills space b/w cells and fibers, viscous
Function:
- Acts as lubricant, barrier and provides structure, diffusion medium for metabolites
What are the molecules that make up ground substance?
- Glycosaminoglycans/mucopolysaccharides
- Proteoglycans
- Multiadhesive Glycoproteins
- Water
Structure and function of glycosaminoglycans
- Linear polymers of disaccharides that have negatively charged carbosyl groups that attract cations, which attract extracellular fluid. Function here = hydrating effect, which allows for compression resistance
Clinical relevance of glycosaminoglycans
- In Grave’s disease, increased deposition of GAGs (hyaluronic acid and chondroitin sulfate) in retroorbital space that causes exophthalmos.
- Excess deposition of GAGs in Grave’s also involves skin
List of glycosaminoglycans
- ) Dermatan sulfate
- ) Chondroitin sulfate
- ) Heparan sulfate
- ) Keratan sulfate
- ) Hyaluronic acid
- ) Heparin
Structure of proteoglycans
- Linear chains of glycosaminoglycans bound to protein core, majority of weight is attributable to CHOs
Types of proteoglycans
- ) Syndecan
- ) Perlecan
- ) Decorin
- ) Versican
- ) Aggrecan
What is syndecan? Function?
- Syndecan is a type of proteoglycan where core protein of molecule is embedded in cell membrane as transmembrane protein
- In fibroblasts, syndecan serves as co-receptor for fibroblast growth factor
What is perlecan? Function?
- Major proteoglycan type found in basement membranes and CT
- Function = cell adhesion, proliferation, glomerular filtration, development and growth factor binding
Clinical relevance of perlecan
- Enhanced in some types of tumors, promoting proliferation and angiogenesis
Function of versican
- Important in cell-cell and cell-ECM interactions
What are multiadhesive glycoproteins?
- Glycoproteins that molecularly tether cell to EC elements
Structure of multiadhesive glycoproteins?
- Have three primary binding sites:
- 1.) one for integrins (cell adhesion molecules)
- 2.) one for collagen fibers
- 3.) one for proteoglycans
List types of glycoproteins
- ) Fibronectin
- ) Laminin
- ) Nidogen (entactin)
- ) Tenascin
- ) Chrondronectin
- ) Osteonectin
List types of glycoproteins. What are their binding domains and where are they located?
1.) Fibronectin
Binding domains: integrins, collagen, heparin, heparan sulfate and hyaluronic acid
Location: CT, blood plasma, embryonic tissue
2.) Laminin
Binding domains: integrins, heparan sulfate, collagen (IV) and entactin
Location: basal lamina
3.) Nidogen (entactin)
Binding domains: laminin and type IV collagen
Location: basal lamina
4.) Tenascin
Binding domains: syndecans and fibronectin
Location: embryonic tissue
5.) Chrondronectin
Binding domains: collagen II, chondroitin sulfates, hyaluronic acid and integrins of chrondrocytes
Location: cartilage
6.) Osteonectin
Binding domains: collagen I, proteoglycans, integrins of bone cells (cytes and blasts)
Location: bone
List fibers of ECM
- ) Collagen
- ) Reticular
- ) Elastic
What is the most abundant protein in the body?
- Collagen (20-25% of all protein), specifically type I
Principle amino acids that make up collagen?
- Principly glycine (every 3rd AA)
- Also hydroxyproline and hydroxylysine (both specific to collagen)
Type I Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: dermis, tendon, bone, dentin, cementum, fibrocartilage, organ capsules
- Synthesizing cells: fibroblasts, odontoblasts, cementoblasts, osteoblasts, chondroblasts
- Function: resistance to tension
- Organization: fibril-forming
Type II Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: hyaline and elastic cartilage
- Synthesizing cells: chondroblasts
- Function: resistance to pressure
- Organization: fibril-forming
Type III Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: spleen, liver, lymph nodes, smooth muscle, skin, lung
- Synthesizing cells: smooth muscle cells, fibroblasts, reticular cells
- Function: maintains structure in expansible organs
- Organization: fibril-forming
Type IV Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: basal lamina
- Synthesizing cells: endothelial cells, epithelial cells, Schwann cells and smooth muscle cells
- Function: support of delicate structures and filtration
- Organization: network-forming
Type V Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: dermis, tendon, bone, fibrocartilage
- Synthesizing cells: fibroblasts, mesenchymal cells
- Function: participates in type I collagen function
- Organization: fibril-forming
Type VII Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: dermis
- Synthesizing cells: epidermal cells
- Function: anchors lamina densa to lamina reticularis
- Organization: anchoring
Type IX Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: hyaline cartilage
- Synthesizing cells: chondroblasts
- Function: binds collagen fibrils to one another
- Organization: fibril-associated
Type XI Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: hyaline cartilage
- Synthesizing cells: chondroblasts
- Function: participates in type II function
- Organization: fibril-forming
Type XII Collagen. Tissue distribution, synthesizing cells, function, organization?
- Tissue distribution: tendons, ligaments
- Synthesizing cells: fibroblasts
- Function: binds collagen fibrils to one another
- Organization: fibril-associated
What happens to the hydrated state of tissue where there is excessive accumulation of GAGs? No change, decrease and increase?
- Increase
What does inactivation of the gene for perlecan result in?
- Defective skeletal development
What amino acid is measured to calculate the concentration of collagen?
- Hydroxyproline or hydroxylysine, both which are specific to collagen
- Glycine is principle AA in collagen, but not specific for it
What are reticular fibers?
- Reticular fiber are composed of type III collagen
What chemical is used to stain reticular fibers?
- Silver (argyrophilic) and PAS (magenta color)
What cell types synthesize reticular fibers? In what tissues are reticular fibers found?
- Fibrocytes, reticulocytes, smooth myocytes and Schwann cells
- Tissues: spleen, liver, lymph nodes, smooth muscle, skin and lung
Elastic fibers. Function, attributes/characteristics, synthesizing cells, molecular composition
- ) Function: imparts tissue with elasticity
- ) Attributes: slender and branched, densely arranged in bundles, nonfibrous elastic tissue arranged in fenestrated sheets (blood vessels), turnover is poor
- ) Synthesizing cells: fibroblasts, smooth muscle cells, chondroblasts
- ) Molecular composition: three components needed to form elastic fibers: a.) proelastin (tropoelastin = cleaved form), b.) microfibril-associated glycoprotein and c.) fibrillin (1&2)
Discuss unique findings of proelastin
- Proelastin is a component of elastic fibers
- Contains unique amino acids desmosine and isodesmosine
Discuss Ehlers-Danlos types IV, VI and VII. What is the defect and what are the clinical consequences?
- ) Type IV
- Defect: mutation in Col3A1 gene encoding type III collagen (aka reticular fibers)
- Clinical: varicose veins, aortic rupture, intestinal rupture - ) Type VI
- Defect: defective hydroxylation of lysine destabilizes strength of collagen
- Clinical: hyperelasticity of skin, rupture of eyeball - ) Type VII
- Defect: mutations in Col1A1 and Col1A2 genes encoding type I collagen
- Clinical: joint dislocation and hypermobility of joints
Scurvy. Defect and clinical consequences?
- Defect: tropocollagen molecules cannot aggregate into fibrils due to decreased hydroxylation of proline caused by deficiency in vitamin C
- Clinical: gum ulceration and hemorrhages
Osteogenesis imperfecta. Defect and clinical consequences?
- Defect: mutations in Col1A1 leads to reduction in the synthesis of type I collagen
- Clinical: spontaneous fractures and cardiac insufficiency
Strickler syndrome. Defect and clinical consequences?
- Defect: mutation in Col2A1 gene encoding for type II collagen
- Clinical: myopia (near-sighted), hypoplasia of mandible, arthritis
Marfan syndrome. Defect and clinical consequences?
- Defect: mutation of the fibrillin 1 gene on c/s 15
- Clinical: aortic aneurysm or rupture, myopia (near-sighted), detached lens, skeletal defects: long thin arms, legs, toes, fingers, pectus excavatum, scoliosis
What stains elastic fibers?
- Resorcin-fuchsin or Verhoeff stains (black)
Discuss difference between the basal lamina and basement membrane. What is the composition?
- ) Lamina lucida: composed of laminin, entactin, integrins and dystroglycans (integrins and dystroglycans are transmembrane receptors for laminin)
- ) Lamina densa: composed of type IV collagen, fibronectin and perlecan
- ) Lamina fibroreticularis: composed of fibronectin and types I and II collagen
- Basal lamina = lamina lucida + lamina densa
- Basement membrane = basal lamina + lamina fibroreticularis
What anchors the basal lamina to the lamina fibroreticularis?
- Anchoring fibrils of type VII collagen, fibrilin and fibronectin
Function of basal lamina and basement membrane?
- Adhesion interface bw epithelium and ECM, molecular filter, regulation of cell differentiation, proliferation, organization and regeneration of cells
What is basal lamina associated with non-epithelial cells called?
- non-epithelial: muscle, adipocytes and Schwann cells
- called external lamina
Clinical relevance of basal lamina and basement membrane?
- Basal lamina prevents spread of epithelial tumors unless broken down
- Goodpasture Syndrome = autoimmune dz in which antibodies develop against specific type IV collagen subunit
- Developmental failure demonstrated in mouse model if laminin is defective or has deficit
What are keloids?
- Excessive deposition of collage in scar formation
Excessive deposition of collagen
- MI
- Keloid/scar formation
A 38 yo male presents with fatigue and edema. Lab studies reveal urine sediments, urine protein, primary albumin. Biopsy of kidney was obtained and sent to pathology. Membranous nephropathy seen: Prominent spikes of silver-staining matrix projecting from basement membrane lamina densa toward urinary space, which separate and surround deposited immune complexes that lack affinity for silver stain. Electron micrograph shows electron-dense deposits along epithelial side of basement membrane. What is the diagnosis?
- Goodpasture’s Syndrome: autoimmune dz in which antibodies develop against specific type IV collagen subunit.
- Leakier kidneys
