Collagen and Elastin (Sayner) Flashcards
4 basic tissues of organs
Muscle
Connective
Epithelial
Nerve
Cells that secrete and organize the ECM
End in suffix “-blast”
i.e. fibroblasts, osteoblasts
Components of the extracellular matrix
Protein fibers (collagen, elastin)
Basement membrane
Adhesive proteins and large sugar molecules
Functions of connective tissue
- Mechanical support- resists tension and compression
- Organizes tissues
- Generates immune response
- Metabolic support- growth factors, hormones, high energy lipids
Fibrillar collagen types
Class: Fibrillar
Types: I, III, V
Network forming collagen
Class: basement membrane
Type: IV
Fibrillar collagen disorders
Osteogenesis Imperfecta
Scurvy
Ehler-Danlos
Network forming collagen disorders
Alport Syndrome
Goodpasture Syndrome
Disorders of elastin
Marfan’s Syndrome
Alpha1 Antitripsin Deficiency
heterotrimer
different types of alpha chains within collagen molecule
Ex: type 1 collagen: COL1A1 + COL1A2
-hundreds of repeats: very rigid
homotrimer
only one gene product makes up
Ex: Type III Collagen: COL3A1
amino acids interrupt the repeats– more flexible, forms networks
Structure of collagen alpha chain
Every third amino acid is Glycine
(Gly-X-Y)n
(Gly-X-Y)n
X and Y are frequently which amino acids?
Proline and Lysine
Mutations in Gly, Pro, and Lys can disrupt formation of collagen
Basement Membrane
secreted by endothelial and epithelial cells
separate the underlying tissue
When does a carcinoma become invasive?
If basement membrane is breached
Breached vessel = metastisis
Basement Membrane collagen type
Collagen IV molecules
Collagen IV molecules
6 different alpha chains forming unique expression patterns
Formation of basement membrane
protomers assemble into sheets –> alternating sheets of collagen IV and laminin interconnected by multi adhesive proteins –> junctions anchor cells into laminin and fibronectin within the basement membrane
Elastin fibers function
resilience and recoil after stretch
Elastin fibers structure
Interwoven with collagen to prevent overdistenstion
Elastin fibers are synthesized by:
Fibroblasts
Chondroblasts
Smooth muscle cells
Fibroblasts
skin, tendons, lungs
Chondroblasts
elastic cartilage (ear, nose, epiglottis)
Smooth muscle cells
blood vessels, respiratory system, hollow organs
Elastin fibers are found in:
the lungs (inhalation and exhalation)
tunica media of aorta
Monomers of elastin
tropoelastin
13 different isomers
Fibrillin Functions
formation of elastin fibers
sequesters TGFbeta
structural integrity of aortic wall and suspensory ligament of lens
Type 1 Collagen
is
found
in:
Bone
Skin
Tendons
Dentin
Fascia
Cornea
LATE wound repair
Mnemonic: bONE
Type II Collagen
Cartilage
Vitreous body
Nucleus pulposis
Mnemonic: carTWOlage
Type III Collagen
Reticulin
skin
blood vessels
uterus
fetal tissue
EARLY wound repair
Type IV Collagen
Basement Membrane
Lens
Mnemonic: Type IV, under the floor
Elastin fiber components
2 alternating hydrophobic segments
Rich in glycine, proline, or other hydrophobic amino acid
Cross-linking of Elastin
LYSYL OXIDASE modifies lysine to desmosine and isodesmosine
Lysine rich domains crosslink alpha helical segment through bi-, tri-, and tetrafunctional cross-links within mature elastin
Formation of elastin fibers from tropoelastin
tropoelastin deposited into fibrillin microfibrils –> fibulin crosslinks fibrillin and elastin subunits –> forms elastin fibers
osteogenesis imperfecta causes
Type I collagen deleterious mutation (90% of OI, types I-IV)
Genes encoding cross-linking proteins and other accessory proteins required for fiber formation (10%)
OI Type I Cause
mildest form
Decreased COL1A1 (COL1A2) synthesis, but collagen molecules are NORMAL
normal genes, just not enough
OI Symptoms
BITE
Bones: brittle, frequent fractures, spinal curvature
I (eyes): blue sclera
Teeth: lack of dentin
Ear: hearing loss (affects ossicles)
Tendons: loose joins
Ddx for OI
child abuse
OI Type II-IV cause
Deletions/mutations in the COL1A1/COL1A2 gene
= ABNORMAL collagen molecules = more severe disease
Shortened pro-alpha1 chain
Replacement of glycine
Altered C-propeptide (aggregation of C-terminus leading to folding of helix)
Lethal type of OI
OI Type II
perinatally lethal
Scurvy Cause
vitamin c deficiency
Proylyl- and lysyl-hydroxylase require vitamin C and iron to HYDROXYLATE ALPHA CHAIN
–> without this, collagen fibers are weak due to lack of crosslinking
scurvy population
young children, homeless, drug/alcohol addicts, >65
-reduced access to fresh fruit
scurvy symptoms
ecchymosis (bruising/discoloration of skin)
bleeding gums
abnormal wound healing
weak joints
Ehlers-Danlos Syndrome is a disorder of (fibrillar/network forming) collagen
fibrillar
Classical EDS
Mutation in COL5A1 or COL5A2 gene
Vascular EDS
Mutation in COL3A1 gene
Collagen III has a core of type V, and type I helps cross link –> forms delicate network of reticular fibers
reticular fibers surround: skin, liver, smooth muscles of arteries, GI tract, lymph nodes
Symptoms of EDS
joint hypermobility +/- dislocation
late walking
skin: hyperextensible, bruises easily
tissues: abnormal bruising/bleeding
unexplained blood vessel rupture, gastrointestinal perforation, organ rupture (vascular type)
Abnormal scarring, splitting wounds
Alport Syndrome type of collagen
Network forming collagen: Type IV
mutation in alpha3, alpha4, or alpha5 (x-linked) chains
Alport Syndrome cause
embryonic collagen form persists in adult
-not as cross-linked, resistant to proteases
LUNGS not affected: can still be fully functional with immature form of collagen
Alport syndrome symptoms
Progressive kidney disease
variable eye and ear defects
Goodpasture Syndrome Collagen Affected
Type IV Collagen
Goodpasture Syndrome pathophysiology
autoimmune disease
Goodpasture antibodies against the NC1 domain of collagen IV alpha3 of the glomerular and alveolar basement membranes
Goodpasture Syndrome symptoms
Pulmonary: dyspnea, hemoptysis (coughing up blood)
Renal: hematuria, proteinuria, renal failure
Marfan’s Syndrome collagen affected
Fibrillin-1 Mutation
Marfan’s syndrome pathophysiology
reduced fibrillin-1 –> release of TGFbeta –> activates growth factor receptors –> growth and proliferation
Alpha1-Antitrypsin Deficiency pathophysiology
GLU342LYS; mutation in SERPINA1
AAT is synthesized in the liver (encoded by SERPINA1) and sent to the lung, where it protects elastin fibers from degradation by elastase
Alpha1-Antitrypsin deficiency symptoms
liver cirrhosis
early onset emphysema
